TABLE OF CONTENTS 

EXECUTIVE SUMMARY .......................................................................................................... 1

BACKGROUND ON PHARMACOLOGY, DRUG RESEARCH, 

AND THE BRANCH.................................................................................................................... 2

PEDIATRIC PHARMACOLOGY ............................................................................................. 5

ACTIVITIES OF THE PPRU NETWORK .......................................................................................... 6 

ACTIVITIES RELATED TO THE BPCA............................................................................................ 8 

OTHER BRANCH EFFORTS IN PEDIATRIC PHARMACOLOGY ........................................................ 13 

OBSTETRIC PHARMACOLOGY .......................................................................................... 17

ACTIVITIES OF THE OPRU NETWORK........................................................................................ 17 

OTHER BRANCH EFFORTS IN OBSTETRIC PHARMACOLOGY ....................................................... 20 

FUTURE DIRECTIONS FOR THE BRANCH....................................................................... 21

PANEL DISCUSSION.................................................................................................................... 22 

CONTINUE SUPPORT OF INVESTIGATOR-INITIATED RESEARCH TO ADDRESS 

 THE KNOWLEDGE GAPS IN OBSTETRIC AND PEDIATRIC PHARMACOLOGY ............................. 23 

PROMOTE TRAINING OF NEW INVESTIGATORS IN OBSTETRIC 

 AND PEDIATRIC PHARMACOLOGY......................................................................................... 25 

INCORPORATE NEW TECHNOLOGY DEVELOPMENTS INTO OBSTETRIC 

 AND PEDIATRIC PHARMACOLOGY......................................................................................... 26 

FIGURES AND TABLES ...............................................................FIGURES AND TABLES-1

APPENDIX A: BRANCH PERSONNEL....................................................... APPENDICES-1

APPENDIX B: BEST PHARMACEUTICALS FOR CHILDREN ACT 

(BPCA) STUDIES.............................................................................................. APPENDICES-3

APPENDIX C: BPCA DRUG PRIORITIZATION LIST ............................. APPENDICES-5

APPENDIX D: BRANCH-SUPPORTED MEETINGS, FISCAL YEAR 2004 

THROUGH FISCAL YEAR 2007.................................................................... APPENDICES-6

APPENDIX E: MEMBERS OF THE EXPERT PANEL ............................. APPENDICES-8

APPENDIX F: BRANCH PUBLICATIONS, FISCAL YEAR 2004 

THROUGH FISCAL YEAR 2007.................................................................. APPENDICES-10

Executive Summary 1 

 

EXECUTIVE SUMMARY 

Mike Leavitt, current Secretary of the U.S. Department of Health and Human Services (DHHS), 

explained the underlying motivation for the Obstetric and Pediatric Pharmacology Branch 

(OPPB), January 19, 2005, when he stated: “When we are alone at night caring for a sick child, 

we trust [the Department] to ensure that the medicine we give her is effective.” 

The OPPB was established in May 2004 within the Center for Research for Mothers and 

Children (CRMC) of the Eunice Kennedy Shriver National Institute of Child Health and Human 

Development (NICHD)1

, National Institutes of Health (NIH). The Branch was created to 

centralize research, clinical trials, and drug development activities for pediatric and obstetric 

pharmacology within a single organizational entity, in a fashion that complemented the longstanding and highly successful clinical trials work of the NICHD-supported Maternal-Fetal 

Medicine Unit (MFMU) Network and the Neonatal Research Network (NRN). The Branch 

combined investigator-initiated research and training with the activities of the Pediatric 

Pharmacology Research Units (PPRU) Network and those related to the Best Pharmaceuticals 

for Children Act (BPCA) with efforts within the newly formed Obstetric Pharmacology Research 

Units (OPRU) Network. 

The overarching goal of the Branch is to provide a research focus—based on cross fertilization 

of clinical, translational, and scientific expertise—to promote new research in basic and 

translational pharmacology with a focus on pregnant women and children. At the same time, the 

Branch is intended to be reactive to emerging issues by providing mechanisms that allow faster 

initiation of studies to address critical research questions. 

In addition to its role in centralizing pediatric and obstetric pharmacology efforts, the NICHD 

leadership designed the Branch to: 

• Identify, prioritize, and sponsor basic, translational, and clinical research and research 

strategies to improve understanding of interactions between therapeutics, disease, pregnancy, 

and development. 

• Facilitate training and other educational modalities that enhance pediatric and obstetric 

pharmacology expertise, as well as skills in reproductive, perinatal, and pediatric 

epidemiology. 

Throughout its first two years, the OPPB initiated a clinical research program to meet the 

congressional mandates set forth for the BPCA, while building on existing research programs in 

obstetric and pediatric pharmacology. These activities also helped to identify knowledge gaps in 

areas of pediatric pharmacology and, subsequently, similar knowledge missing from obstetric 

pharmacology. Multiple other challenges—including feasibility, ethics, and study design—also 

had to be dealt with before some of the Branch’s more complex, multi-stage clinical trials could 

begin. 

1

 By act of congress (Public Law 110-154), the Institute was renamed the Eunice Kennedy Shriver National Institute 

of Child Health and Human Development (NICHD) in December 2007. 
Because the Branch is a relatively new entity within the NICHD, its goals and portfolio are still 

evolving as new areas of need are identified in pediatric and obstetric pharmacology research and 

training. Nevertheless, the Branch has made significant progress toward achieving many of its 

initial goals. This report summarizes the productivity of the Branch-supported Networks and 

grants, as well as the successful implementation of current initiatives. 

In addition, this report highlights the Branch’s efforts to identify future strategic directions and to 

implement evolving goals that advance pediatric and obstetric pharmacology. Specifically, the 

Branch intends to build upon the foundations that the NICHD has fostered in obstetric and 

pediatric pharmacology since the 1970s through renewed efforts of the PPRU Network, through 

research conducted by the OPRU Network and BPCA activities, through training opportunities, 

and through investigator-initiated research. With guidance from an expert panel, which met in 

July 2007, the OPPB also identified several substantive areas that require increased emphasis, 

including (but not limited to) investigator-initiated research into therapeutics, an increased 

emphasis on obstetric pharmacology research, and training grants to develop new obstetric and 

pediatric pharmacologists. A discussion of these and other key areas for future research is 

available in the Future Directions for the Branch section of this report. 

BACKGROUND ON PHARMACOLOGY, DRUG RESEARCH, AND THE BRANCH 

All substances are poisons; there is none which is not a poison. The right dose 

differentiates a poison and a remedy.

Paracelsus (1494-1541), considered the “father of pharmacology”2

Pharmacology is the scientific study of drugs and their effects, especially in the treatment of 

disease. For a drug to be effective, it must be present in the body at an appropriate 

concentration, meaning it must be properly absorbed, distributed, metabolized, and then 

eliminated—a process called pharmacokinetics. Similarly, an effective drug must be able to 

reach its appropriate target and produce the desired effect by relying on biochemical and 

physiological interactions between the drug and the body—a process called pharmacodynamics. 

Through the study of pharmacokinetics and pharmacodynamics, advances in pharmacology have 

introduced new opportunities to treat diseases and improve health. These advances have also led 

to a new field of pharmacology—called pharmacogenomics—that relates drug effects to specific 

genetic patterns. Understanding how genetics contributes to variability in drug response 

provides a new tool for effectively using therapeutics and offers hope of decreasing the risk for 

unexpected toxicities. 

Developmental aspects of drug disposition and response have largely been excluded from 

pharmacology research. The changing nature of immature organisms adds a unique complexity 

to pediatric and obstetric pharmacology research and requires a systems-biology approach to 

 

1 Kearns, G. L., S. M. Abdel-Rahman, et al. (2003). Developmental pharmacology - Drug disposition, action, and 

therapy in infants and children. New England Journal of Medicine, 349(12), 1157-1167. 

2 Background on Pharmacology, Drug Research, and the Branch 
fully understand the inter-relationships of the variables involved. The lack of knowledge in the 

field has been borne out by medication disasters, such as administration of chloramphenicol to 

newborns who lacked mature metabolic pathways and developed cardiovascular collapse, or who 

were exposed in utero to teratogens, such as retinoic acid and angiotensin-converting enzyme 

inhibitors and suffered the resultant anomalies. 

Since its establishment, the Eunice Kennedy Shriver National Institute of Child Health and 

Human Development (NICHD) has been the key sponsor of maternal and pediatric research at 

the National Institutes of Health (NIH). The Pregnancy and Perinatology Branch, in the Center 

for Developmental Biology and Perinatal Medicine, supports two Networks in related areas: the 

Maternal-Fetal Medicine Units (MFMU) Network, which was formed in 1986 to focus on 

clinical questions in maternal-fetal medicine and obstetrics, particularly with respect to the 

continuing problem of preterm birth; and the Neonatal Research Network (NRN), also formed in 

1986, which performs multi-center clinical trials in neonatal medicine in order to reduce infant 

morbidity and mortality and to promote healthy outcomes. 

Because the NICHD had an important stake in the safety and efficacy of drugs used in children, 

the Institute leadership decided to go beyond its existing commitment and regulations to address 

gaps in information about the pharmacokinetics, safety, and efficacy of drugs used in pediatric 

patients. The NICHD established the Pediatric Pharmacology Research Units (PPRU) Network 

within its Center for Research for Mothers and Children (CRMC) in 1994 to conduct clinical 

trials and related translational research in pediatric therapeutics. The Network not only sought 

answers to key questions about pediatric drugs, but it also established and improved the 

infrastructure for such research, which would facilitate and promote pediatric labeling of drugs. 

For more information on the Network’s activities and progress, see the Activities of the PPRU 

Network section of this document. 

The PPRU also brought the issue of pediatric pharmacology research to the attention of the 

pharmaceutical industry. In addition to conducting studies, the PPRU: provided a locus for preand post-marketing clinical trials in children by pairing pediatric clinical pharmacologists with 

the pharmaceutical industry and contract research organizations; served as an advisory body 

between the pharmaceutical industry, regulatory agencies, health professionals, and the public on 

the appropriate use of drugs in children; encouraged and identified areas for research beyond the 

Network’s activities; served as a resource for training health care providers and other 

professionals; and created opportunities for fellows, medical students, and residents to obtain 

relevant training. Through the PPRU’s more than 10 years of projects, the NICHD helped to 

establish pediatric pharmacology as a scientific discipline and revolutionized how such studies 

were conducted. 

In 1997, the Food and Drug Administration Modernization Act (FDAMA) permitted the U.S. 

Food and Drug Administration (FDA) to grant six months of additional market exclusivity to 

companies that conduct pediatric studies to help encourage the pharmaceutical industry to seek 

pediatric labeling for its products. At the same time, the FDA adopted an administrative rule to 

require that holders of New Drug Applications include information on testing in children. The 

“Pediatric Rule” was struck down in court, but was subsequently enacted by congress as part of 

the Pediatric Research Equity Act. 

Background on Pharmacology, Drug Research, and the Branch 3 
In 2002, the Best Pharmaceuticals for Children Act (BPCA) directed the Secretary of Health and 

Human Services, working through the Director of the NIH, to establish a program for pediatric 

drug testing and development. The NIH Director selected the NICHD to implement this new 

program. For more information on the Act, see the Activities Related to BPCA section of this 

report. Once the NICHD received the delegation of authority, it immediately began planning to 

establish the Obstetric and Pediatric Pharmacology Branch (OPPB). 

The Branch was established in 2004 to provide an organizational focus for advancing scientific 

and medical understanding of safety and effectiveness of drugs used in infants, children, 

adolescents, and pregnant women. This focus was intended to complement existing activities 

throughout NICHD and to build on the historical contributions of the Institute in obstetric and 

pediatric pharmacology. Research topics for the Branch included: the nature of growth and 

development, such as molecular signaling that induces growth and differentiation; development 

of receptors and transporters and their relationships to genetic polymorphisms, mechanisms of 

effect (for good or bad), and detoxification pathways in the human; and research on homologous 

pathways in young animals to facilitate extrapolation—all topics in need of dedicated basic 

research. Analogous areas of clinical focus included assessments of clinical trial feasibility 

including pharmacoepidemiology; clinical trial designs, including observational study methods; 

and development and validation of biomarkers, non-invasive measures of drug effect, and 

clinical assessment scales. The Branch identified the “systems” approach as the best way to 

improve the safety and effectiveness of pharmaceuticals, and as a way to promote new research 

on medications used during pregnancy and in children. A systems-biology approach would 

allow the field to re-assemble all the component parts into an integrated whole. 

The overarching goal of the Branch is to provide a focus for the cross fertilization of clinical, 

translational, and scientific expertise in pediatric and obstetric pharmacology research. Among 

the Branch’s early objectives were the following: 

• Enable safe and effective treatment of disease during pregnancy, infancy, and childhood, 

using pharmaceuticals that are appropriately tested within their target populations. 

• Provide training that will create specialists who understand the unique qualities of these 

populations and develop therapies specific to their needs. 

• Offer mechanisms that enable research to address emerging issues quickly, effectively, and in 

manners that are scientifically sound. 

Among the Branch’s first activities was the establishment of the Obstetric Pharmacology 

Research Units (OPRU) Network, with the goal of identifying, characterizing, and studying 

drugs used during pregnancy. For more information on the Network, see the Activities of the 

OPRU Network section of this report. 

In 2007, the BPCA was reauthorized with the passage of the FDA Amendments Act 

(P.L. 110-85), which included language on research related to biologics and pediatric medical 

devices and expanded the focus of BPCA activities to address a wider range of pediatric 

therapeutic needs, in addition to pediatric drugs. 

4 Background on Pharmacology, Drug Research, and the Branch
The Branch’s method for achieving its goal is to stimulate and fund basic, translational, and 

clinical research and training in pediatric and obstetric pharmacology, of which the BPCA is 

only one aspect. (Other NIH Institutes and Centers contribute funding to BPCA-specific 

activities.) Since it was established, the Branch’s total funding has ranged from $29.49 million 

in fiscal year 2004, to $37.08 million in fiscal year 2007 (see Figure 1 and Figure 2). The 

primary future focus of the Branch will be to continue and expand efforts to enlarge the research 

portfolio. 

The remainder of this document—the OPPB’s first report to the National Advisory Child Health 

and Human Development (NACHHD) Council—highlights the Branch’s accomplishments and 

research highlights in pediatric pharmacology and obstetric pharmacology. The Branch’s 

training efforts in pediatric and obstetric pharmacology and in reproductive, perinatal, and 

pediatric epidemiology are included within the descriptions of pediatric and obstetric 

pharmacology. 

The final section of the report, Future Directions for the Branch, examines possible future 

research areas for the Branch and outlines strategies that will enable the OPPB to pursue its goals 

and mission for the next four years. 

PEDIATRIC PHARMACOLOGY 

Historically, pediatric pharmacology research has been hampered by a variety of issues, ranging 

from the absence of a financial incentive for drug companies, to unknown pharmacokinetic and 

pharmacodynamic differences, to ethical issues of non-therapeutic research and informed 

consent. As a result, nearly 80 percent of drugs lack data on appropriate dosing, efficacy, and 

safety for neonates, infants, children, or adolescents. Further, approximately 30 percent of new 

molecular entities licensed in the United States between 1998 and 2002 did not have a 

formulation suitable for pediatric use. 

The OPPB supports a growing portfolio of efforts intended to address these concerns. The 

Branch supports projects in diverse areas of pediatric drug development, including animal 

models to evaluate toxicity, innovative research in the development of novel compounds and 

devices, research in pharmacoepidemiology, as well as clinical trials. Many of these efforts are 

conducted through the PPRU Network and through the BPCA. A listing of current PPRU sites 

and BPCA studies appears in Figure 4 and Appendix B, respectively. 

The following sections highlight the Branch’s activities related to pediatric pharmacology 

research. 

Pediatric Pharmacology 5 
ACTIVITIES OF THE PPRU NETWORK

Since its establishment, the NICHD has encouraged and supported research in pediatric 

pharmacology. That support has continued through to the present with research on topics such as 

pediatric AIDS, and through Institute-supported networks, such as the PPRU Network and the 

NRN. The PPRU Network, established in 1994, currently includes 13 sites (see Figure 4) whose 

overarching goal is to determine how childhood development affects drug disposition, response, 

and the interplay between drug, development, and disease. As mentioned earlier, the PPRU 

Network helped to not only bring the issue of pediatric pharmacology research to the attention of 

industry, but also to change the way that pharmacology research is conducted in pediatric 

populations. 

Network researchers perform a variety of studies, including (but not limited to) pharmacokinetic 

studies (phases 1 and 2 of drug development), pharmacokinetic-pharmacodynamic 

investigations, studies of trial design, studies of drug metabolism, and pharmacogenetics 

evaluations. Therapeutic areas studied by the PPRU sites include interventions for common 

disorders (i.e., allergies, asthma, and upper respiratory infections) and for less common disorders 

(i.e., cystic fibrosis, severe infections, HIV/AIDS, and sickle-cell anemia). 

In addition, although the Network includes studies across all age groups, the unique experience 

and qualifications of its investigators enables PPRU studies to include children younger than two 

years of age, including a number of studies in the newborn—an area of pediatric research that 

has been historically neglected, but is better served now by the PPRU, the NRN, and the OPPBled Neonatal Drug Development Initiative (NDDI); see the Research in Special Populations

section of this document and Appendix D for more information. 

Network accomplishments include the following: 

• Total enrollment of patients (1994 through June 2007) = 9,292 

• Total studies performed (1997 through June 2007) = 264, including 161 designed/ 

co-designed by an industry sponsor, and 103 designed by investigators 

• Journal articles published = 621; this number includes articles on the following topics: 

o Basic/translational: 27.5 percent 

o Pharmacokinetics: 38.5 percent 

o Pharmacodynamics: 1.0 percent 

o Animals: 9.2 percent 

o Clinical trials: 23.2 percent 

o Antibiotic resistance: 0.3 percent 

o Study design: 0.3 percent 

• The Network has contributed to pediatric labeling of 23 drugs. 

• The Network has trained 77 pediatric clinical pharmacology fellows, including 52 M.D.s, 

five Ph.D.s, three M.D./Ph.D.s, 16 Pharm.D.s, and one Ph.D. candidate. 

Recent PPRU Network efforts include the following: 

• Studying children with atopic dermatitis to define a basis for the significant variability in 

response to antihistamines 

6 Pediatric Pharmacology
• Using new imaging techniques for non-invasive approaches to assess gastric emptying 

• Evaluating early pharmacotherapy for autism using buspirone, guiding the therapies with 

biomarkers of disease, and measuring responses with positron emission tomography (PET) 

scan 

• Conducting multi-center pharmacokinetic studies of the use of the antifungal medicine, 

fluconazole, and other antimicrobials in preterm newborns to assess how gestational and 

postnatal age, kidney function, surgery, and concomitant medications impact drug disposition 

• Developing population pharmacokinetic/pharmacodynamic models to assess the effects of 

polymorphisms in drug-metabolizing enzymes on drug clearance and adverse event profiles, 

research that could allow for personalized dosing and improved patient outcomes 

• Developing and evaluating the use of nanotechnology, such as drug dendrimers, which are 

complexes for targeted drug delivery for treatment of diseases, while taking into account 

recent findings that indicate drug-dendrimer complexes enter cells more rapidly than do 

parent drugs 

• Developing initiatives to identify and evaluate the determinants of inter-individual 

differences in response to opioids across the age spectrum to aid development of acute and 

chronic pain models of disease for neonates and children 

• Creating a warehouse of standardized clinical, pharmacogenetic, and pharmacokinetic, and 

pharmacodynamic data that will allow for simulation modeling, data mining, and trend 

analysis and that will assist in identifying and qualifying safety biomarkers, which can be 

used in designing clinical trials and in monitoring post-marketing safety 

When the PPRU was developed in 1994, its main focus was enhancing the infrastructure 

available for research related to pediatric drug development. Those activities have been highly 

successful. Such studies focused on the effect and disposition of drugs to treat disease processes 

and comprise the traditional types of studies that the PPRU Network has conducted. Take the 

case of CYP2D6—a prime example of a clinically relevant drug-metabolizing enzyme for which 

genotyping and phenotyping information, resulting from PPRU Network studies, has the 

potential to improve drug safety and efficacy. CYP2D6 is involved in the biotransformation of 

more than 40 therapeutic entities, including Selective Serotonin Re-uptake Inhibitors (SSRIs), 

atomoxetine, risperidone, codeine, and dextromethorphan, which are commonly used in pediatric 

populations. Considerable variability in CYP2D6 gene expression and activity results from more 

than 60 well-known genetic polymorphisms. 

From a developmental perspective, in vitro studies indicate that very limited CYP2D6 activity is 

present in the fetal liver (at approximately 1 percent of adult values), but that CYP2D6 protein is 

detectable in all liver samples from newborns. During the first 28 days of life, both CYP2D6 

protein and catalytic activity progressively increase to 20 percent of the activity observed in 

adults. In contrast, in vivo results, derived from a PPRU Network longitudinal phenotyping 

study of more than 100 infants during the first year of life, suggest that the CYP2D6 phenotype 

is concordant with genotype by two weeks of age (Blake et al. [2007]. Clinical Pharmacology 

and Therapeutics, Apr;81[4], 510-516). Phenotyping data from older children suggest that 

CYP2D6 catalytic activity in children is comparable to adults by at least 10 years of age, and 

probably much earlier. 

Pediatric Pharmacology 7 
Understanding the relationship between CYP2D6 genotype, phenotype, and drug clearance is as 

important clinically for pediatrics as it is for adults. Evidence from several sources suggests that 

drug accumulation and the risk of concentration-dependent toxicities are clearly associated with 

significant morbidity and mortality in children. CYP2D6 and possibly developmental or 

pharmacogenetic factors (or both) could contribute to the increased risk of serious toxicity in this 

age group. 

To ensure that the PPRU Network continues to meet the needs of the pediatric pharmacology 

research community, the Network is going through a strategic planning process. Consultations 

with experts in the field suggest that the Network’s efforts may be more beneficial if aimed at 

pediatric therapeutics, which relates diseases or conditions to therapy and includes evaluating the 

need for treatment. This new emphasis of the PPRU Network is exemplified by a recent study of 

scalp ringworm disease. 

Trichophyton tonsurans is the most common cause of tinea capitis in the United States, and its 

natural history has not yet been determined. Characteristics of scalp ringworm disease are 

different in preschoolers than in other age groups and are associated with chronic background 

colonization and periodic symptomatic disease that improves spontaneously. To learn more 

about this phenomenon and how it affects treatment, researchers followed 446 children at a 

single preschool (for children age two years) and collected samples of T. tonsurans isolates for 

genotyping. 

In older children, T. tonsurans carriage rate is low and symptoms occur at the time of fungal 

infection; treatment with antifungal drugs is standard practice in such cases. The researchers 

found that the natural course of the disease in preschoolers was different. The preschoolers had a 

high T. tonsurans background carriage rate. Further, symptoms occurred at any time and were 

unrelated to acquisition of infection or particular strain types, meaning that treatment with 

antifungal drugs is unnecessary and ineffective in this population (Abdel-Rahman et al. [2006]. 

Pediatrics, 118, 2365-2373). 

Building on the successes of the PPRU Network will require critical evaluation of the basic and 

translational needs in pediatric drug development and represents the first step in an analysis 

being conducted by OPPB to determine the Network’s next investment in pediatric drug 

research. 

ACTIVITIES RELATED TO THE BPCA

In 2002, the NIH Director delegated the NICHD to lead its activities related to the BPCA. The 

original legislation for BPCA outlined the following tasks: identifying and prioritizing drugs 

that need study; developing studies in collaboration with experts at the NIH, the FDA, and other 

organizations; and conducting studies on priority drugs after manufacturers decline to do so. 

Since that time, the NICHD (in collaboration with 17 participating Institutes and Centers) has 

worked closely with the FDA and other organizations to create an authoritative list of off-patent 

8 Pediatric Pharmacology
drugs (those without marketing protections or exclusivity) as the first step in the process of 

prioritizing drugs for study in children. 

Within NIH, the prioritization process involves a number of steps: 

• Identifying an off-patent drug. Although the process for developing an authoritative listing 

of off-patent drugs has presented challenges, there has been significant progress. Since 2003, 

drugs placed on the Priority List have been published in the Federal Register. (See 

Appendix C for the list.) 

• Determining relevant indications for the drug in pediatric populations. In prioritizing offpatent drugs for study in pediatric populations, careful attention was given to the 

identification of relevant diseases and conditions that affect children. The NICHD evaluated 

data on the use of certain drugs in adults to identify those of potential value to children, 

resulting in the potential indications or diseases for study in children (note that some of these 

diseases are unique to children). 

• Reviewing available data about use of drugs in children. For each drug, the Branch 

reviewed and evaluated data describing how the drug is used, its pharmacokinetics in 

children, and its safety and effectiveness to determine the nature of pediatric testing needed. 

For diseases/conditions in children that did not have comparable diseases/conditions in adults 

(or the disease or condition does not occur in adults), the Branch evaluated the scientific 

literature to determine if the drug was likely to be beneficial for pediatric populations. 

Once these steps are completed, the OPPB begins studies to gather data related to using the drugs 

in pediatric populations. Some of the studies the Branch is supporting include the following: 

• Pre-clinical studies (in animals or cell culture) determine the metabolic pathways and 

pharmacokinetic and pharmacodynamic properties of a drug. Although pre-clinical studies 

are required for all drugs approved by the FDA today, many of the drugs prioritized for study 

under BPCA have long been on the market, so even basic pre-clinical data are missing. For 

example: 

o Morphine has been available for many years. However, recent clinical studies suggest 

that newborn infants and especially preterm infants may have unexpected adverse 

responses, including an increased risk of poor neurologic outcome, when treated with 

morphine. The Branch is supporting basic science efforts to determine the differences in 

pain receptors that exist between infants and adults. 

o Similarly, although ketamine has been used for sedation of children for many years, 

toxicological data obtained from rodent models during the last decade have suggested 

that anesthetics and sedatives induce central nervous system apoptosis. The NICHD has 

supported extensive non-human primate studies to assess the effects of this drug on the 

developing brain, in an animal model similar to a young human child. Current data 

demonstrates that non-human primates do experience windows of vulnerability to 

ketamine-induced apoptosis and necrosis, marking one significant difference from 

observations of rodent models. These windows of vulnerability occur shortly after birth, 

and sensitivity decreases substantially with increasing age following birth. 

• Phase 1 studies are pharmacokinetic and safety studies and may include preliminary efficacy 

data if patients with the disease of interest are enrolled. All of the prioritized drugs require 

pharmacokinetic studies in children across developmental stages (e.g., neonate, infant, child, 

Pediatric Pharmacology 9 
and adolescent). In some instances, the current tablet and capsule formulations are not 

appropriate; the dosage form may be difficult to swallow, or the correct dose difficult or 

impossible to measure accurately. The development of new formulations for children or for 

those with specific conditions (e.g., children with cerebral palsy, infants with sickle-cell 

disease, and young children with neuroblastoma) is also needed. 

• Phase 2 studies are small safety and efficacy studies, which employ and refine appropriate 

dosing as determined by Phase 1 studies. Because efficacy and safety may be dependent on 

age and developmental status/stage, these studies need to enroll children of various ages/age 

groups. For example, existing safety and efficacy data for dactinomycin (also known as 

actinomycin-D) from the National Cancer Institute (NCI) Children’s Oncology Group (COG) 

are being analyzed to determine the drug’s safety profile—specifically, the relationship of 

age, diagnosis, and dose of actinomycin-D to incidence of severe hepatic toxicity. 

• Phase 3 clinical studies are larger, “pivotal” studies that provide a definitive assessment of 

the safety and efficacy of a treatment for a given condition. The Branch supports several of 

these studies, including (but not limited to) the following: 

o Lorazepam is used to sedate pediatric patients in intensive care units, and to treat severe 

seizures in children, although it has not been tested in children for either use. The Branch 

supported studies to assess the dosing and metabolism of this drug in children and is now 

supporting clinical trials to test safety and efficacy. 

o Nitroprusside is used to lower blood pressure to decrease the risk of bleeding during 

surgery. The OPPB sponsored a recently completed clinical trial of nitroprusside doseresponse, safety, and efficacy. Results from the trial are expected soon. 

o Lithium is frequently used to treat bipolar disease. Given this drug’s toxicity, it is 

possible that the dosage currently used in children, which is based on adult data, is too 

high. The Branch is currently supporting clinical trials to assess the proper safe and 

effective dose for children with this condition. 

o Baclofen was introduced into clinical use more than 30 years ago and is currently used to 

treat spasticity in children with cerebral palsy. Despite the age of the drug and its 

frequent use in children, data supporting dosing, efficacy, and safety in children has not 

been characterized. The Branch, working with experts in pediatric neurology, pediatric 

pharmacology, pharmacogenomics, and occupational and physical therapy, is conducting 

the needed studies. In conducting these clinical studies, the Branch has had to develop a 

liquid formulation of the drug; the only commercially available formulation is a tablet, 

which difficult for children to consume, especially those with cerebral palsy. 

o Hydroxyurea has shown great benefit in treating adults with sickle-cell disease, based on 

studies conducted by the National Heart, Lung, and Blood Institute (NHLBI). The 

Branch is partnering with NHLBI to evaluate dosing, efficacy, and safety of hydroxyurea 

in children younger than one year of age. Because the only form of the drug 

commercially available was a tablet, the NICHD-NHLBI partnership developed a liquid 

formulation for administering to these very young children. 

Progress from BPCA Studies 

Research findings for a few specific drugs provide excellent examples of the flexibility of the 

Branch’s activities under the BPCA and the importance of the studies it supports. 

10 Pediatric Pharmacology
METHYLPHENIDATE

Methylphenidate—more commonly known as Ritalin®—is widely prescribed to children and 

adolescents for the treatment of attention deficit/hyperactivity disorder (ADHD). ADHD is the 

most commonly diagnosed behavioral disorder of childhood, and more than 5 million 

prescriptions for methylphenidate are written annually in the United States alone. The drug has a 

long record of beneficial impact on behavior, from reductions in hyperactivity and impulsivity to 

increases in attention and self control. Despite its benefits and its broad use among a vulnerable 

population, few studies have explored its long-term safety or effects. 

The majority of past reports of the drug’s adverse events were consistent with the drug’s 

pharmacological mechanism, namely those related to stimulants, such as decreased appetite and 

sleeplessness. However, recent research has suggested that adverse events extend to several 

unanticipated outcomes, including genetic toxicity, sudden cardiac arrest, and issues of growth 

and pubertal progression. 

Researchers from one 2005 study reported a significant increase in genetic damage in its sample 

of 12 children (ages six to 12 years) diagnosed with ADHD and treated with methylphenidate, 

with each child acting as his/her own control. The investigators measured the frequency of 

aberrations in cultured blood lymphocytes of the children before treatment began and after three 

months of continuous treatment, with doses ranging from 20 mg/day to 54 mg/day (El-Zein et al. 

[2005]. Cancer Letters, 230[2], 284-291). In humans, increases in chromosomal aberrations and 

micronuclei in cultured blood lymphocytes are associated with an increased risk of cancer. 

This study raised important questions about the long-term safety of methylphenidate that experts 

at the NIH and the FDA took very seriously. The questions were so concerning that experts took 

the unusual step of asking to visit the researchers’ laboratory to discuss the findings and review 

the data. Since then and with OPPB support, researchers have conducted a number of studies 

investigating the potential clastogenicity of methylphenidate. The Branch’s flexibility under the 

BPCA enabled these studies to be conducted on a faster timeframe than is usual for federally 

funded studies. Thus far, the results from these and other studies are reassuring. For instance: 

• Suter and colleagues reported no increases in structural or numerical chromosomal 

aberrations in cultured human blood lymphocytes exposed to methylphenidate at high 

concentrations. The authors also reported that, when they gave mice a dose of 

methylphenidate more than 100 times that administered to pediatric patients, the frequency of 

chromosomal alterations did not significantly increase, not even among bone marrow 

erythroblasts, a rapidly dividing cell population more prone to such aberrations (Suter et al. 

[2006]. Mutation Research-Genetic Toxicology and Environmental Mutagenesis, 607[2], 

153-159). 

• In another study, Andreazza and colleagues measured DNA damage in brain and peripheral 

blood cells of juvenile and adult rats after single- and repeated-dose treatments with 

1 mg/kg/day, 2 mg/kg/day, or 10 mg/kg/day methylphenidate (1 mg/kg was comparable to a 

clinical dose of 54 mg in a 30 kg pediatric patient). The technique used permitted the 

researchers to detect frank strand breaks, lesions, and incomplete repair sites in DNA, as well 

as the frequency of micronuclei in cultured blood lymphocytes. Although the researchers 

reported no increase in micronucleated lymphocytes for any of the treatment groups, the 

authors did report increases in DNA damage in cells of the brain and peripheral blood 

Pediatric Pharmacology 11 
• One study tried to replicate the results of the research that originally raised the red flags 

(Walitza et al. [2007]. Environmental Health Perspectives, 115[6], 936-940). Researchers 

conducting this prospective study examined the frequency of micronucleated lymphocytes in 

cultured blood of pediatric patients (ages five to 17 years) sampled prior to and after 

methylphenidate treatment for one, three, and six months. Dosages varied from 5 mg/day to 

40 mg/day for immediate-release formulations, and 18 mg/day to 54 mg/day for long-acting 

versions. This study was also larger in size and longer in duration than the previous study. 

Results failed to show any significant treatment-related increases in frequencies of 

micronucleated cells in the pediatric patients. 

Based on what is now known about the pharmacology and metabolism of methylphenidate 

(National Toxicology Program, Center for the Evaluation of Risks to Human Reproduction. 

[2005]. NIH Publication No. 05-4473.), there is little evidence that the drug interacts with DNA 

by either a direct or indirect mechanism. As a result of Branch-supported activities, there is also 

a growing body of evidence that methylphenidate does not induce chromosomal alterations in the 

blood cells of experimental animals or humans treated with the drug. 

METHOTREXATE

In the United States, 12,000 new cases of childhood cancer are diagnosed annually. Although, 

on the positive side, many of those children survive their disease, on the negative side, 

considerations of long-term drug toxicities are important and unknown. Methotrexate is a 

mainstay of pediatric leukemia treatment, but causes neurocognitive toxicity, as measured by 

neurocognitive testing. 

The drug is administered intravenously in different ways, including as a high dose with 

leucovorin rescue, and to the maximum-tolerated dose without leucovorin rescue (called the 

“Capizzi method”). The Branch is supporting an ongoing clinical study with the NCI COG to 

determine which of these two regimens causes less neurocognitive damage in children who have 

high-risk B-cell and T-cell acute lymphoblastic leukemia, without reducing long-term survival. 

SODIUM NITROPRUSSIDE

Physicians commonly need to reduce a patient’s blood pressure, such as in the operating room to 

reduce intra-operative blood loss, and in the intensive care unit. Clinicians have used sodium 

nitroprusside as a hypotensive agent for many years, but the drug lacks pediatric labeling for 

dosing, safety, and efficacy. 

The Branch is sponsoring two clinical trials in children who are receiving sodium nitroprusside 

as part of routine clinical care. The goal of Study 1 is to determine the nitroprusside doseresponse relationship. This randomized, blinded study of four dose levels of nitroprusside for 

12 Pediatric Pharmacology
children ages birth to 17 years, who are undergoing operative procedures requiring blood 

pressure reduction, recently completed enrollment (n=203) following two years of recruitment. 

The goal of Study 2 is to determine if tachyphylaxis (loss of sensitivity to the blood-pressure 

lowering effect of the drug) occurs in children who receive sodium nitroprusside during longterm continuous infusions in the intensive care unit. 

Challenges involved in performing these studies include time constraints related to consent, 

allowing time for the infusion preparation, and issues of anesthesiologists’ access to surgical 

patients. 

OTHER BRANCH EFFORTS IN PEDIATRIC PHARMACOLOGY

In addition to its studies conducted through the PPRU Network and related to the BPCA, the 

OPPB also supports efforts in the following areas. 

Toxicity Research 

The OPPB supports a number of grants that are using animal models to evaluate and understand 

various aspects of toxicity in a developing organism. For instance, using infant rat and pregnant 

guinea pig models, one investigator is studying how the developing brain is vulnerable to 

potential neurotoxic actions of drugs during synaptogenesis (a brain growth spurt), which occurs 

at different times in different species. The hypothesis is that the drug suppresses neuronal 

activity to lower-than-normal physiological degrees, thereby disrupting synaptogenesis, and 

causing immature neurons to receive an internal signal for apoptosis or programmed cell death. 

This process is a concern because an increase in cell death in a developing brain may have 

consequences across the lifespan. Another investigator is evaluating the potential toxicity of 

stimulants on dopamine axons in the non-human primate model. 

Novel Research 

The OPPB has awarded numerous Small Business Innovative Research (SBIR) grants for 

researchers to conduct novel research in the area of pediatric pharmacology drug development. 

One investigator is working to synthesize a novel low-molecular-weight compound that can be 

used to treat Respiratory Syncytial Virus (RSV) infection in children. RSV infection alone 

results in more than 126,000 hospitalizations and 500 deaths annually in infants and young 

children. Currently, ribavirin is the only FDA-approved agent for treating RSV, and its efficacy 

in young children who have the virus is questionable. The drug is also difficult to administer and 

costly. The investigator’s plan is to complete key in vitro studies in the cotton rat model to 

determine activity, and then develop in vivo studies for potential clinical use. 

Investigators were funded to conduct other novel research, such as: using nanotechnology to 

develop a device that will deliver a controlled amount of subcutaneous insulin to patients; 

developing the technology to miniaturize a biocompatible device; developing hybrid drugs that 

can be used in the future for the treatment of ADHD; and conducting stereospecific studies to 

asses the regulation of transporter genes in the disposition of psychostimulants. 

Pediatric Pharmacology 13 
Research in Special Populations 

The Branch has several initiatives that focus on the neonatal population, which is certainly a 

therapeutic “orphan”; only a small fraction of drugs used in this population are approved for use, 

leaving large gaps in dosing, safety, and efficacy information. One investigator is developing a 

tool for early detection of nephrotoxicity in newborns treated with aminoglycoside (AG). The 

current tools, including serum-concentration monitoring and urinalysis, are neither sensitive nor 

specific to AG toxicity. The investigator is using state-of-the-art proteomics (tools that separate 

and identify differentially expressed proteins as candidate markers of toxicity) approaches for the 

characterization of normal and AG-treatment induced urine changes in newborns. 

In addition to the lack of safety and efficacy studies, pharmacokinetic studies are also rare in the 

neonatal population. The Branch is funding a researcher who will be conducting a 

pharmacokinetic study to determine the proper dose of azithromycin for treating preterm 

neonates infected with Ureaplasma urealyticum—a bacterium believed to be involved in the 

development of chronic lung disease in neonates. 

Epidemiology Research 

The Branch has an interest in how epidemiological research can augment clinical research, in 

addition to how it might identify gaps in fields of interest to help direct future clinical research. 

For instance, using a hospital database, one investigator is conducting a multi-site, retrospective, 

cohort study to understand clinical outcomes and adverse events related to treatment with 

osteltamivir in children who are hospitalized with influenza infection. This research is both 

timely and innovative because administering osteltamivir to hospitalized children has not been 

investigated, even though the burden of illness is high and the global implications related to a 

potential pandemic are considerable. Additionally, recent reports suggest that an unusual form 

of central nervous system toxicity is present in preadolescent children treated with oseltamivir; 

this research may help to understand this phenomenon. 

Other Branch epidemiological research has developed databases that describe health services’ 

utilization among children and the medications associated with their interactions with the health 

system. For example, recent research evaluated use of psychotherapeutic medications among 

Medicaid-insured preschoolers (two years to four years of age) using data from seven different 

state Medicaid programs. Among these children, more than 2 percent received a 

psychotherapeutic medication on one or two occasions. This usage of psychotherapeutic 

medications is double that reported in an earlier analysis of Medicaid data. Increased use also 

suggests, given the lack of knowledge of the effects of these drugs on the developing brain, the 

need for more detailed understanding of appropriate use, dosing, safety, and efficacy of these 

drugs in young children. 

Another example of pharmacoepidemiological research conducted by the Branch explores the 

use of asthma medications among children who have the diagnosis of asthma. Asthma is one of 

the most common chronic conditions in children; it is the third leading cause of hospital 

admission for children and often impacts throughout the lifespan of the individual. Current 

asthma treatment and prevention guidelines emphasize the need for controller medications 

among children with asthma; yet in the study, fewer than 60 percent of the children with a 

diagnosis of asthma were treated with controller medications. This finding is consistent with 

14 Pediatric Pharmacology
other observations suggesting that children with asthma may be receiving suboptimal care. 

These types of data also emphasize the need for the Branch to work closely with other groups, 

such as the NHLBI, the National Institute of Allergy and Infectious Diseases (NIAID), the 

American Academy of Pediatrics, American Academy of Family Practitioners, pharmacists who 

may be involved in counseling patients and families about asthma medications, and other groups 

with a focus on asthma, to improve pediatric therapeutics. 

In addition, the OPPB has also collaborated with contractors Research Triangle Institute 

International, Inc., and Westat, Inc., to construct more precise estimates of the frequency of 

conditions affecting children in the United States, and the frequency of use of certain 

medications in U.S. children. This activity was an essential, arduous, and expensive process, 

given the daunting complexities of choosing datasets, setting useful parameters, and resolving 

methodological problems. These data were gathered both in response to the requirements of the 

BPCA, and to better inform the development of the drug prioritization list. The Branch is now 

working to translate these findings and databases into resources that interested pediatric 

researchers can use. The OPPB’s current approach contemplates developing both training 

sessions for potential users, as well as appropriate public-use datasets. 

Training 

One of the Branch’s key mandates is to promote and promulgate the fields of pediatric and 

obstetric pharmacology. Within the PPRU Network, support for such training comes in the form 

of the Mentored Scientist/Clinical Investigator Development Award (MSCIDA) mechanism 

(U10). This small research grant is given to a young investigator so that he/she can study 

pediatric pharmacology and learn about pediatric drug development. 

Each year, the PPRU sites can nominate one young investigator for consideration for this award. 

The applications are reviewed and the award given to the most deserving applicant. This 

innovative mechanism helps young investigators get additional support for focused training in 

pharmacology. To date, the MSCIDA has supported seven pediatric clinical pharmacology 

fellows, six M.D.s, and one M.D./Ph.D. 

Collaborations 

The Branch has played a leadership role in several collaborative efforts within the federal 

government by assembling experts in pediatric health and ethics from the United States, Europe, 

and Canada: 

• In 2004, the Branch sponsored an NDDI meeting with representatives from industry, 

academia, the FDA, and the NIH. Thus far, the outcome of this ongoing Initiative has been a 

summary published as a special supplement of Pediatrics and more detailed descriptions of 

research needs published in Clinical Therapeutics. The Branch also intends to follow-up on 

the Initiative to: 

o Perform clinical studies based on the templates developed by the Working Groups (e.g., 

pain, bronchopulmonary dysplasia, and neonatal seizures). 

o Determine the feasibility of studying specific drugs in low-birthweight infants based on 

current use by indication in neonatal intensive care units across the United States. 

o Develop novel study designs that take into account the small number of patients who are 

available, ethical limitations, standard practices, and feasibility issues. 

Pediatric Pharmacology 15 
o Create initiatives to address knowledge gaps, which will be identified at an upcoming 

meeting of the Working Groups for this Initiative. 

• Also in 2004, the Branch (in collaboration with FDA) sponsored a meeting on the use of 

animal models to understand developmental differences in safety and efficacy of drugs. For 

a complete list of Branch-supported meetings and conferences, see Appendix D. 

• In December 2005, the NICHD conducted a Pediatric Formulation Initiative with 

representatives from the government, industry, and academia to explore a range of issues and 

challenges related to creating pediatric drug formulations. The effort sought to identify 

issues and discuss the many barriers that block access of children and infants to important 

drugs. This Initiative is ongoing. 

• In January 2006, the Branch supported a follow-up workshop, Emergency Research in 

Children: Ethical, Regulatory, and Clinical Challenges, to identify issues and concerns 

related to the conduct of research involving children under the Emergency Exception from 

Informed Consent (EFIC) statute allowed under FDA and DHHS regulations. Invited 

participants included investigators, ethicists, and Institutional Review Board members. 

• The January 2006 meeting led to a subsequent meeting, held in September 2006, with federal 

representatives from the NIH, FDA, the Health Resources and Services Administration 

(HRSA), the DHHS Office of Human Research Protections, investigators, and ethicists. The 

purpose of the meeting was to discuss the investigators’ approach to emergency EFIC in the 

Branch’s lorazepam–status epilepticus study. This study, approved by the FDA, is the first to 

be conducted in pediatric patients under emergency EFIC requirements. 

• In March 2006, the Branch convened a meeting of international leaders in pediatric 

pharmacology research to determine how to successfully establish a global consortium for 

addressing important issues in clinical pharmacology, therapeutics, and toxicology relevant 

to the health of children. Groups currently engaged in international pediatrics research, 

teaching, and clinical activities are essential for developing such a global consortium on 

pediatric pharmacology. Engaging these international organizations is critical for potential 

infrastructure assistance and to benefit from lessons learned in international pediatrics. 

• The Branch has collaborated with the Canadian Institute of Health Research and the NICHD 

Division of Epidemiology, Statistics, and Prevention Research (DESPR) to offer Summer 

Institutes in Obstetric Pharmacology and in Reproductive, Perinatal, and Pediatric 

Epidemiology during the summers of 2005, 2006, and 2007. The Branch, DESPR, and the 

Canadian Institute are now planning the fourth set of Summer Institutes for 2008. These 

sessions have been extremely useful in addressing the lack of training and investigatorinitiated research in both areas. 

16 Pediatric Pharmacology
OBSTETRIC PHARMACOLOGY 

Pharmacoepidemiological surveys indicate that nearly two-thirds of all pregnant women take at 

least four drugs during pregnancy and labor, and that medication use frequently continues during 

breastfeeding. Because the use of these drugs is largely based on an empiric approach, rather 

than on a scientific basis, and because much of the use does not take into account the profound 

physiologic changes characteristic of pregnancy, the lack of appropriate testing of drugs in 

populations of pregnant women is a significant concern. 

A key issue of drug testing in this population is accounting for the physiological changes during 

pregnancy that influence pharmacokinetics and pharmacodynamics. For example: the gastric 

emptying time and intestinal transit time are increased during pregnancy, which could affect the 

gastrointestinal absorption of drugs; glomerular filtration rate and renal plasma flow increase 

from the sixth week of pregnancy to delivery, meaning an increase in the renal excretion of some 

drugs, such as beta-lactam antibiotics and lithium. 

Further complications arise because the physiological changes characteristic of a normal 

pregnancy may be different in a pregnancy complicated by various conditions and disease states. 

So, just as information about pregnant women cannot be extrapolated from information about 

non-pregnant women, information on the disposition and effects of drugs in abnormal 

pregnancies cannot be extrapolated from data on normal pregnancies. Effects of the pathologic 

abnormalities associated with the disposition and action of drugs in abnormal pregnancies is an 

even less-studied aspect of obstetric pharmacology. 

In determining the types of pharmacology research that should be conducted in obstetrics, the 

field needs to consider that pregnant women have a significantly different set of complexities 

compared to other populations, and that, because of these complexities, pregnant women should 

be studied separately from other populations. Obstetric pharmacology needs large studies of 

pregnant women that have sufficient statistical power to answer important questions. Studies 

should also focus on issues specific to pregnant women, such as pregnancy-specific conditions 

(i.e., preeclampsia) and medications given during labor, to really make progress in understanding 

dosing, effectiveness, and safety. 

ACTIVITIES OF THE OPRU NETWORK

Throughout its history, the NICHD has fostered research in pregnancy. Current intramural and 

extramural activities are reflected in training and research supported by the Branch, by DESPR, 

and through the MFMU Network. The OPRU Network, created in 2004, aims to enhance and 

focus efforts related to obstetric pharmacology (see Figure 5 for a map of Network sites). 

The structure of the OPRU Network differs from most other NICHD-supported efforts in that it 

mandates pairing a clinical Principal Investigator (PI) with a basic science co-PI to facilitate the 

translational nature of the work. The Network seeks to identify, characterize, and study those 

Obstetric Pharmacology 17 
drugs that are of therapeutic value during pregnancy, and whose clinical pharmacology (both 

pharmacokinetics and pharmacodynamics) is altered by the normal and abnormal pregnant states. 

Based on the data needs related to this population, key goals of the OPRU Network are to: 

• Serve as a resource for pharmacologic studies of drug disposition and effect during normal 

and abnormal pregnancies. 

• Conduct multi-site cooperative clinical studies that advance the knowledge of 

pharmacokinetics and pharmacodynamics of drugs used during pregnancy. 

• Conduct pharmacogenetic studies of the effects of pregnancy on drug delivery and action on 

the mother as well as on the developing fetus. 

• Perform studies of placental transfer of drugs. 

• Facilitate translational research so that clinical materials can be utilized for basic research 

studies. 

• Enhance the exchange of information among basic scientists, neonatologists, and 

obstetricians. 

• Serve as a resource for training health care providers in the field of obstetric pharmacology. 

The following institutions were selected during the initial funding cycle of the OPRU Network: 

• University of Washington 

• Georgetown University 

• University of Texas Medical Branch at Galveston 

• University of Pittsburgh 

Initial efforts of the Network focused on creating a collaborative environment by implementing a 

systems-biology approach in obstetric pharmacology to provide pharmacokinetic and 

pharmacodynamic information currently lacking for obstetric therapeutics, as well as a more 

detailed understanding of disease-pregnancy-therapeutics interactions. Pregnancy is a perfect 

example of systems biology in action in that three entities function together in a complicated 

maternal-fetal-placental unit. Because systems biology attempts to understand and evaluate the 

coordinated system of transporters, channels, receptors, and enzymes acting together as 

gatekeepers to endogenous and foreign molecules, and to unite biological fields instead of 

approaching each one separately, the OPRU Network has developed its protocols and scientific 

interests to take full advantage of the systems-biology approach. These efforts include a study of 

the oral hypoglycemic glyburide, which is used to treat gestational diabetes, and the drug thought 

to be active in preventing prematurity, 17-alpha hydroxyprogesterone caproate. 

Additionally, each Network site has identified up to 10 drugs that are frequently used during 

pregnancy (a total of approximately 30 drugs) for which basic pharmacokinetic and 

pharmacodynamic studies are now being performed. These studies are conducted using a 

generic set of pharmacology protocols, called “opportunistic protocols,” and each OPRU site is 

responsible for developing assays and standard operating procedures for these studies. When 

completed, each of these studies will contribute important information to guide therapy during 

pregnancy. One clever aspect of these studies is that the researchers study pregnant women who 

require one of the 30 drugs as standard treatment for her own health; thus, the required informed 

consent focuses primarily on risks and inconvenience associated with blood sampling, rather 

18 Obstetric Pharmacology
than on the non-therapeutic use of the drug. These opportunistic protocols allow each site to 

play to its own strengths and unique patient populations. For example, one university has a large 

transplant service and has enrolled many women treated with immune modulators. There is also 

efficiency to this process because each site is responsible for studying approximately eight drugs, 

but can cross enroll subjects from their site into studies from the other sites. 

Since the Network was established, its researchers have conducted a considerable amount of 

basic, translational, and clinical research, including studies in non-human primates and other 

experimental animal models to better understand the changes common during pregnancy that 

impact pharmacokinetics and pharmacodynamics. In 2005, as a result of this basic research, 

researchers developed a second clinical protocol and Investigational New Drug application for 

17-alpha hydroxyprogesterone caproate. 

At the time this report to the NACHHD Council was written, researchers from the OPRU 

Network had authored 19 publications and 20 abstracts. 

Current Protocol Summaries 

The OPRU Network currently supports the following protocols: 

• Glyburide. Although gestational diabetes remains a difficult metabolic condition to treat, 

effective management is required to prevent adverse pregnancy outcomes. At present, little 

is known about pharmacokinetics and pharmacodynamics of oral hypoglycemics used during 

pregnancy. The Network’s research efforts have clarified pharmacokinetics and 

pharmacodynamics of these drugs in human and non-human pregnancies and have 

demonstrated placental transport and metabolism, as well as metabolism by other organs. 

The data collected allow researchers to describe systems-biology models of pregnancy, 

gestational diabetes, and therapeutic approaches—all major advances in understanding. 

• 17-Alpha Hydroxyprogesterone Caproate. Despite efforts and attention on many levels, rates 

of preterm birth in the United States continue to increase. Recent data suggest that caproate 

may, in select groups, decrease the risk of preterm birth; however, researchers know little to 

nothing about the pharmacokinetics and potential mechanisms of action of this drug. 

Network investigations are providing needed information on metabolism, pharmacokinetics, 

pharmacodynamics, and mechanisms in humans and non-human primates, and for pregnant 

and non-pregnant states. These data will be shared with the FDA as it considers the strength 

of evidence and mechanistic information concerning the potential utility of this drug. 

Researchers will also use these data to create a systems-biology model, which will provide a 

mechanistic base for further investigations of preterm birth. 

• Opportunistic studies. As explained earlier, the OPRU Network performs these types of 

studies as preliminary evaluations before identifying drug-condition studies, which may later 

get full or systems approaches for evaluation.

Obstetric Pharmacology 19 
OTHER BRANCH EFFORTS IN OBSTETRIC PHARMACOLOGY

In addition to its studies conducted through the OPRU Network, the OPPB also supports efforts 

in the following areas. 

Animal Research 

The OPPB has funded research to evaluate the functions and nuances of the complex systemsbiology model of mother-fetus-placenta. One investigator is using imaging to understand the 

cellular and metabolic derangements that occur during inflammatory processes, and that lead to 

brain injury during fetal development. The hypothesis is that endotoxin-induced intrauterine 

inflammation activates microglial cells in the fetal brain; this activation progresses to nerve-cell 

and white-matter injury, called periventricular leukomalacia. The theory is that, if the activation 

can be decreased or turned off, the degree and magnitude injury will subsequently decrease. The 

investigator is using PET scans to assess microglial response in the rabbit model, using PET 

tracer PK11195. The researcher believes that using neuroimaging to assess inflammatory 

processes could aid the future development of novel therapies. 

Another researcher is evaluating the effects on the fetus of SSRI treatment in the mother during 

pregnancy. One theory suggests that a fetus exposed to SSRIs will have excess serotonergic 

activity and, consequently, will show signs of serotonergic withdrawal after the drug is 

discontinued or after the fetus is delivered. The study is using the baboon model to quantify and 

compare the fetal metabolism of two SSRIs with the fetal and maternal metabolic enzyme 

activity of the drugs. The study will also examine changes in parameters of autonomic 

regulation to assess fetal effects. 

Novel Research 

The Branch continues in its mission to advance the science in the field of obstetric drug 

development. One innovative award seeks to determine fetal pharmacotherapy through 

transplacental drug delivery strategies. The Branch also supports an investigator who is 

exploring the association between prenatal exposure to prescription drugs and teratogenicity and 

chronic diseases of the offspring later in life. Using linked administrative databases, the 

researcher will assess the associations of maternal use of SSRIs on congenital lung and heart 

malformations. Using epidemiological data to evaluate potential toxicities is innovative in the 

field of obstetrics—especially because most safety studies in pregnant women have several 

limitations, such as recall bias of drug exposure and a sample size often too small to detect rare 

adverse events. 

Training 

Currently, the Branch offers Institutional Training Grants (T32) through its Predoctoral Training 

Program in Reproductive, Perinatal, and Pediatric Epidemiology. These grants establish a new 

predoctoral program that will train outstanding candidates in the discipline of epidemiology and 

will mentor them in team research that integrates basic, clinical, and population sciences. This 

program will prepare the students to be both teachers and independent researchers. 

20 Obstetric Pharmacology
After three rounds of review, the Branch selected four sites for the program: Emory University, 

the University of Washington, Boston University, and the University of Pittsburgh. Although the 

program’s initial focus was reproductive, perinatal, and pediatric epidemiology, the Branch 

intends to expand the program to include pharmacoepidemiology and health services impacts, as 

well as pre- and postdoctoral training. 

In addition, since July 2005, the Branch has co-sponsored the annual Summer Institutes in 

Maternal-Fetal Pharmacology and in Reproductive, Perinatal, and Pediatric Epidemiology, held 

in conjunction with the Canadian Institutes of Health Research and DESPR to help increase the 

infrastructure in obstetric pharmacology and epidemiology. 

FUTURE DIRECTIONS FOR THE BRANCH 

The OPPB’s activities are guided by a strategic planning process, which focuses on critical 

research issues in obstetric and pediatric therapeutics, tempered with the congressional mandate 

for BPCA and subsequent legislation. In accordance with the NICHD’s process for increasing 

accountability and transparency in strategic planning for its Branches, the OPPB sought expertise 

and feedback on its future directions from a panel of experts in the fields of obstetrics, 

gynecology, drug development, microbiology, birth defects, pharmacokinetics, and pediatrics. 

The panel, which met in July 2007, also included members of the NACHHD Council, public 

representatives, and patient advocates (see Appendix E for a list of panel members). 

The meeting provided the Branch with an opportunity to review its activities, progress, 

challenges, and areas of need and to lay out goals for the future. Meeting participants discussed 

the Branch’s activities and goals within the framework of three overarching questions: 

• Given its mission, what are the most important scientific opportunities that the Branch should 

try to pursue during the next four years? 

• Given its mission, what are the most important public health issues that the Branch needs to 

address during the next four years? 

• What areas deserve less emphasis because progress has been made or will continue without 

further stimulation from the Branch or from the NICHD? 

The first part of this section provides a summary of the expert panel discussion; the remaining 

sections describe goals for the Branch for the next four years. 

Future Directions for the Branch 21 
PANEL DISCUSSION

The panel began with a discussion of the Branch’s research from the perspective of the drugdevelopment pipeline (see Figure below). Much of the Branch’s research has focused on the 

clinical and applied side of the process, including research using mature products to better 

understand use, safety, and efficacy during pregnancy and in children. Overall research at NIH, 

however, focuses on basic and translational activities. The panel encouraged the Branch to 

transition some of its research and training activity in the direction of more basic and 

translational research. From the perspective of 21st century biomedical science, such research 

would provide the foundation for future product development, while also clearly emphasizing the 

respective roles of NIH and industry in drug development. 

Figure A: Drug Development Pipeline 

An important issue now facing the Branch is how to build on the foundation it has created since 

2004, and on previous work done in the NICHD on obstetric and pediatric drug development. 

The panel emphasized the need to integrate obstetric and pediatric pharmacology by enhancing 

the focus on pharmacoepidemiological research initiatives. The panel also noted that the 

opportunity to encourage and support basic and mechanistic research related to pediatric and 

obstetric pharmacology represents a critical need. By integrating the Branch’s portfolio more 

thoroughly—the PPRU Network, the OPRU Network, the BPCA activities, and the investigatorinitiated efforts—the Branch will make more progress toward achieving its goals. 

The panel noted a need to identify knowledge gaps in relevant diseases and respective treatments 

in pediatric and obstetric pharmacology. Such a review is necessary to ensure the best allocation 

of available resources. In addition, the participants discussed the successes and challenges 

associated with existing research efforts to identify new ways of promoting collaborations and 

partnerships, and talked about how to use existing mechanisms to develop innovative approaches 

for conducting research and training. 

22 Future Directions for the Branch 
Using input from the panel, the Branch identified three key goals for advancing knowledge in 

obstetric and pediatric pharmacology:

• Continue support of investigator-initiated research to address the knowledge gaps 

• Promote training of new investigators 

• Incorporate new technology developments 

The remainder of this report outlines possible activities for the Branch within these key areas of 

research. 

CONTINUE SUPPORT OF INVESTIGATOR-INITIATED RESEARCH TO ADDRESS THE KNOWLEDGE 

GAPS IN OBSTETRIC AND PEDIATRIC PHARMACOLOGY

Although knowledge gaps exist in both pediatric and obstetric pharmacology, the gaps in 

obstetric therapeutics are substantial and deserve more emphasis than they have received in the 

past. For example, the current guidelines for treating anthrax do not consider pregnancy; 

therefore the current dosing recommendations might be ineffective in pregnant women. 

Similarly, despite progress made specifically through the efforts of the PPRU Network, 

challenges also remain in pediatric pharmacology. For example, the current assumptions and 

tools used to study many drugs used in children are ineffective for determining safety and 

efficacy. 

During the next four years, the Branch plans to expand its portfolio of investigator-initiated grant 

research with a focus on the following areas. 

Study Design and Outcome Measures 

The Branch will consider these activities: 

• Continue to promote research that highlights the differences in pharmacokinetics and 

pharmacodynamics, as well as toxicity and adverse events in children and pregnant women. 

These areas of interest must include the characterization of disease processes and the 

influence of development on disease processes. 

• Encourage innovative research to improve the tools and methodology available for analyzing 

therapeutic outcomes after treatment during pregnancy and in children, including analysis of 

drug safety. Identifying important pediatric and obstetric diseases and focusing the Branch’s 

resources to match the tools available with the medical need are vital steps to accomplishing 

this goal. 

• Create initiatives to encourage research on developing relevant therapeutic measurement 

tools for use in pregnancy and childhood. Many drug trials fail, not because they are 

ineffective, but because the evaluations of efficacy are inappropriate for pregnancy or 

children. 

• Continue studies in animal models and efforts to determine what role these model systems 

play in extrapolation to human studies, particularly in the area of a developmental 

pharmacology. 

Future Directions for the Branch 23 
• Diversify the Branch portfolio, devoting more funds to obstetric pharmacological research, to 

help balance current funding proportions, emphasizing studies across the course of 

pregnancy, labor, and breastfeeding. 

• Consider creating a bio-bank as an important, cost-effective, and economical approach to 

acquiring samples for pharmacology research, beginning with a repository for OPPB trials to 

collect samples for pharmacokinetic, pharmacodynamic, and pharmacogenomic analyses. 

• Shift the focus of the PPRU Network from clinical trials to cross-disciplinary research. This 

type of research is critical for advancing drug development in pediatrics and fosters the 

Network’s collaboration with industry, the FDA, and practitioners. The OPRU Network will 

also continue its cross-disciplinary approach for addressing therapeutic concerns unique to 

pregnancy. 

• Create integrated teams of investigators with overlapping and complementary expertise to 

strengthen the focus on research collaboration, cross fertilization of knowledge, information 

exchange, and hypothesis generation. 

• Increase efforts in obstetric and pediatric pharmacoepidemiology. This field is largely 

underdeveloped and unaddressed, but has the potential to answer many of the questions 

related to these populations. For example: 

o The common off-label use of drugs represents a significant public health concern and 

clinical dilemma, but an equally untapped research resource. Large 

pharmacoepidemiology databases, both existing and new, could be used to quantify offlabel use and, more importantly, study its effects. 

o Pharmacoepidemiological analysis of drug use and its unique consequences in children 

and during pregnancy could be appropriately structured to help evaluate efficacy and 

safety. The Branch plans to fund research to enhance understanding of how these data 

resources can contribute to knowledge of therapeutics. 

• Foster research to enhance safety evaluations and pharmacokinetic research of drugs in 

obstetrics and pediatrics. Many drugs studies lack pharmacokinetic data, while others relied 

on flawed study designs to obtain their data. Collecting these data is a challenge given the 

small number of patients available for study in pediatrics and obstetrics. However, linking 

innovative epidemiological approaches to clinical trials will aid in evaluating drug safety and 

efficacy from a cross-disciplinary perspective. 

Partnerships and Collaborations 

The Branch will consider these activities: 

• Continue and expand partnerships with experts in multiple specialties of pediatric 

therapeutics to develop and implement clinical trials. With the very recent reauthorization of 

the BPCA, the NIH is taking a more proactive role in the development of proposed pediatric 

study requests, so enhancing these collaborations will be critical. The Branch will also seek 

to expand linkages with cooperating NIH Institutes and Centers in the pediatric arena and to 

include appropriate obstetric collaborations. 

• Partner with agencies whose activities are treatment related. Because Branch-supported 

research will impact treatment, collaborations with organizations such as the Agency for 

Healthcare Research and Quality (AHRQ), which recently spent $13 million on the Centers 

for Education and Research Therapeutics for conducting research and education that will 

advance the optimal use of drugs, medical devices, and biological products, are vital. The 

24 Future Directions for the Branch
AHRQ is creating a network of 100 million participants to link data resources for studying 

drug safety. By partnering with AHRQ, the OPPB could enhance the focus on obstetric and 

pediatric populations. 

• Refine and expand partnerships with the FDA. Such efforts will help to identify study design 

and labeling opportunities and will make industry participation in obstetric and pediatric 

therapeutic research more attractive. 

• Enhance partnerships that the Branch has already developed with the American Academy of 

Pediatrics (AAP), the American College of Obstetricians and Gynecologists (ACOG), 

relevant research societies, and clinical pharmacology societies. 

• Consider partnerships to foster therapeutics in pediatrics and obstetrics, perhaps providing 

funding options, such as a supplement to Clinical and Translational Science Awards, or 

limited competition research funding consistent with Institutional Awards. 

Other Priority Areas 

In an effort to increase staffing and to develop the infrastructure needed to support research, the 

Branch will consider the following activities: 

• Maintain Branch statisticians. Using these resources for multi-center studies could be more 

economical than funding individual statisticians or data coordinating centers. 

• Create a bio-bank collected from studies funded by the Branch and by other NICHD Centers, 

Branches, or programs. This resource would be helpful to investigators interested in 

pharmacological studies. 

• Consider opportunities in new arenas outside of traditional research studies, specifically in 

the area of ethics. For example: 

o The expert panel suggested forming an oversight committee that would review the 

Branch’s activities and make specific suggestions on how to share resources or develop 

new opportunities based on currently funded research. 

o The panel also noted that OPPB research has already encountered and would continue to 

encounter situations, which, if fully analyzed, could contribute to understanding research 

ethics involved in studies during pregnancy and childhood. The panel strongly endorsed 

the concept of adding an ethical, legal, and social component to the Branch. 

• Disseminate the information coming from cross-disciplinary, basic, translational, and clinical 

research through partnerships and collaborations. 

PROMOTE TRAINING OF NEW INVESTIGATORS IN OBSTETRIC AND PEDIATRIC 

PHARMACOLOGY

Because the fields of obstetric and pediatric pharmacology have been relatively invisible until 

recently, a dearth of trained specialists exists that can best be addressed through formal training 

programs in obstetric and pediatric clinical pharmacology. The expert panel indicated that the 

Branch should assist in the development of these training activities. Branch staff also indicated 

an interest in exploring links with clinical pharmacology training programs supported by the 

National Institute of General Medical Sciences. In addition, training programs should address 

the emerging areas of obstetric and pediatric pharmacoepidemiology. In developing training 

programs, the OPPB could also leverage resources; the investment is important because a solid 

Future Directions for the Branch 25 
two- to three-year training grant can give a researcher a career. These training opportunities may 

also contribute to the development of resources needed to do larger studies. 

Panel members also noted increasing challenges related to becoming salaried on K and T tracks. 

Although the creative resources at the NIH have been revolutionary, science careers are not 

being sought out by as many young investigators as in the past. The panel added that the Branch 

might consider allowing a provision for administrative supplements to existing grants as a bridge 

between funds for training and a salaried research grant. 

The Branch will also consider expanding its training portfolio in the following ways: 

• Place a greater focus on balancing pediatric and obstetric research by increasing the portfolio 

of research in obstetric therapeutics. 

• Encourage translational research, including a strategic principle that would require 

connections and collaborations among fields. The Branch could also stress the importance of 

cross-disciplinary training for those who apply for its grants and training programs. 

• Develop programs to train existing obstetricians and pediatricians in new fields of biomedical 

and clinical science, such as pharmacogenomics, metabolomics, informatics, and systems 

biology. 

• Partner with organizations, such as the AAP, ACOG, and the Association of Professors of 

Gynecology and Obstetrics to develop resident training programs. 

• Include more K awards, including the Mentored Clinical Scientist Development Award 

(K08), the Mentored Patient-Oriented Research Career Development Award (K23), and the 

Institutional Mentored Clinical Scientist Development Award (K12), in the Branch portfolio. 

• Track awardees’ career progress to better evaluate efforts to increase training and to ensure 

that Branch funds are being used effectively. 

INCORPORATE NEW TECHNOLOGY DEVELOPMENTS INTO OBSTETRIC AND PEDIATRIC 

PHARMACOLOGY

The expert panel discussed the challenges of refocusing the Branch’s efforts on the discovery of 

new molecules for consideration in obstetric and pediatric therapeutics, recognizing that with the 

increasing information from genomics, proteomics, metabolomics, systems biology, and 

informatics, researchers would be better able to design needed drug research approaches. 

Informing these efforts with information from these new fields enables the Branch to embrace 

21st century medical science. 

To better utilize new technology developments and to encourage novel research, the Branch will 

consider the following activities: 

• Stimulate and explore innovative research designed to enhance drug discovery for obstetric 

and pediatric populations. Research priorities will include (but are not limited to): 

o Determining the numbers of children and women with a given condition 

o Identifying whether established therapies in that drug class exist for obstetric and 

pediatric populations 

o Creating novel methods of drug development specific for obstetrics and/or pediatrics 

26 Future Directions for the Branch
• Establish criteria to mark and follow progress, such as noting project accomplishments that 

change the paradigm of current thinking or fill gaps in a much needed area of research or 

clinical care. Areas of interest include (but are not limited to): 

o Pharmacogenomics in pregnancy and across development 

o Research practice-related findings in obstetric and pediatric therapeutics 

o Analysis of current disease drug treatment guidelines to determine if existing 

recommendations have an appropriate evidence base for obstetrics or pediatrics 

• Apply the latest techniques of laboratory-based and translational science, including 

pharmacogenetics, to the Branch’s pediatric and obstetric pharmacology research activities. 

• Strengthen application of genetic data and biomarkers to patient care and build upon existing 

knowledge in these areas. 

• Include translational research, specifically the effects of the environment, reproductive 

toxicants, nutrition, and weight on drug metabolism, in OPPB efforts to embrace the vision 

of contemporary biomedical science. Other areas of interest include (but are not limited to): 

o Studies of drug use during breastfeeding 

o Evaluation of treatment effects on mother and fetus of drugs intended for fetal benefit 

o Development of new methodologies to determine the safety and efficacy of drugs used in 

obstetrics and pediatrics 

• Create Program Announcements to address the dearth of informatics in pediatric and 

obstetric pharmacology. 

• Encourage innovation in pediatric and obstetric therapeutics, with a continued focus on 

disease- and patient-oriented approaches. 

Future Directions for the Branch 27 

FIGURES AND TABLES 

FIGURE 1: BRANCH FUNDING BY TYPE, FISCAL YEAR 2004 THROUGH FISCAL YEAR 2007

$25.00 $25.00 $25.00 $25.00

$4.48

$10.93 $11.14 $11.10

$0.01 $0.14 $0.75 $1.28

$0

$5

$10

$15

$20

$25

$30

$35

$40

$45

2004 2005 2006 2007

Fiscal Year

Amount 

(In Millions of U.S. Dollars)

BPCA Grants & Contracts Training Other Research

$37.38 $36.89 $36.08

$29.49 

Note: “Other Research” and “Training” funds support competitive proposals, which fall within the referral 

guidelines of the Branch. Included in the “Other Research” category are the two Branch-supported Networks 

(PPRU and OPRU). The “BPCA Grants & Contracts” are utilized to support competitively awarded preclinical and 

clinical research proposals requested by congress in the BPCA and its reauthorization. 

Figures and Tables-1 
FIGURE 2: PROPORTION OF BRANCH FUNDING BY TYPE, FISCAL YEAR 2004 THROUGH 

FISCAL YEAR 2007

Fiscal Year 2004 

Total=$29.49 

BPCA 

Grants & 

Contracts

84.77%

Training

0.03%

Other 

Research

15.19%

Fiscal Year 2005 

Total=$36.08 

BPCA 

Grants & 

Contracts

69.31%

Training

0.39%

Other 

Research

30.30%

Fiscal Year 2006 

Total=$36.89 

BPCA 

Grants & 

Contracts

67.77%

Training

2.03%

Other 

Research

30.20%

Fiscal Year 2007 

Total=$37.38 

BPCA 

Grants & 

Contracts

66.88%

Training

3.42%

Other 

Research

29.70%

Note: All amounts in millions of U.S. dollars. 

“Other Research” and “Training” funds support competitive proposals, which fall within the referral 

guidelines of the Branch. Included in the “Other Research” category are the two Branch-supported 

Networks (PPRU and OPRU). The “BPCA Grants & Contracts” are utilized to support competitively 

awarded preclinical and clinical research proposals requested by congress in the BPCA and its 

reauthorization. 

Figures and Tables-2 
FIGURE 4: PEDIATRIC PHARMACOLOGY RESEARCH UNITS (PPRU) NETWORK SITES

Children’s Hospital

Children’s Mercy of Michigan

Hospital

Rainbow Babies & 

Children’s Hospital 

Children’s 

Hospital of 

Philadelphia

Children’s 

Research 

Institute 

Duke 

University 

Children’s Hospital 

Medical Center

University of 

Louisville

Arkansas

Children’s 

Hospital 

University of Texas 

Southwest Medical Center Baylor College

of Medicine

University

of Utah

University of

California,

San Diego

Figures and Tables-3 
FIGURE 5: OBSTETRIC PHARMACOLOGY RESEARCH UNITS (OPRU) NETWORK SITES

University of

Pittsburgh

Georgetown 

University 

University of Texas 

Medical Branch

University of

Washington

Figures and Tables-4 
Appendices-1 

APPENDIX A: BRANCH PERSONNEL 

(In Alphabetical Order) 

George P. Giacoia, M.D., is project director of the PPRU Network at the NICHD. His research 

interest is in the area of neonatal and pediatric pharmacology. He is a fellow of the American 

AAP and has served as the NIH Liaison to the AAP Committee on Drugs since July 1999. Dr. 

Giacoia completed a residency in pediatrics and a fellowship in neonatology at the Johns 

Hopkins University residency program. He received additional training in pediatric 

pharmacology at Buffalo Children’s Hospital. Dr. Giacoia is board certified in pediatrics and 

neonatal-perinatal medicine. He is the author of approximately 160 articles, book chapters, and 

abstracts. He has been a reviewer for several journals, including Pediatrics, Journal of 

Pediatrics, Developmental Pharmacology, Clinical Pediatrics, Obstetrics and Gynecology, and 

the American Journal of Obstetric and Gynecology. Previous appointments include clinical 

professor of pediatrics at Georgetown University, professor of pediatrics at the University of 

Oklahoma, and Director of Neonatology at the Buffalo Children’s Hospital. 

Jan Leahey is currently the program coordinator for the OPPB at the NICHD. She oversees all 

administrative activities for the Branch including the budget, contracts, and staffing. Previously, 

Ms. Leahey served as the executive secretary of the National Children’s Study Federal Advisory 

Committee. Ms. Leahey received her bachelor’s degree from the University of Maryland. She 

has worked in different places within DHHS, including the Office of the Assistant Secretary of 

Health and Human Services and the Health Resources and Services Administration (HRSA). 

Ms. Leahey worked in the area of government contracts for more than 10 years and, during the 

1990s, was designated as a DHHS Contracting Officer. Prior to working in the OPPB, Ms. 

Leahey was a contracting officer for the NICHD. 

Donald R. Mattison, M.D., Captain, USPHS, was appointed senior advisor to the NICHD 

director and to the director of the CRMC in 2002 and became chief of the OPPB in 2004. He 

provides oversight on obstetric and pediatric pharmacology programs within the NICHD. As 

USPHS Captain, he has been deployed on various missions to provide medical and public health 

support. In 2005, he was awarded the PHS Achievement Medal for his role in the National 

Children’s Study. Dr. Mattison has held numerous academic, clinical, and research 

appointments, including medical director of the March of Dimes, dean of the Graduate School of 

Public Health at the University of Pittsburgh, and professor of obstetrics and gynecology and 

interdisciplinary toxicology at the University of Arkansas for Medical Sciences. He was elected 

as a fellow of the American Association for the Advancement of Science in 1997, a fellow of the 

New York Academy of Medicine in 1999, and a member of the Institute of Medicine in 2000; he 

also received a Distinguished Alumni Award from Augsburg College in 2005. He is the author 

of more than 200 peer-reviewed articles. Dr. Mattison earned a B.A. (chemistry and 

mathematics) from Augsburg College in Minneapolis, Minnesota; an M.S. (chemistry) from the 

Massachusetts Institute of Technology; and an M.D. from the College of Physicians and 

Surgeons, Columbia University. His did his clinical training in obstetrics and gynecology at the 

Sloane Hospital for Women in the Columbia-Presbyterian Medical Center in New York. He did 

his training in pharmacology and toxicology at the NIH. 
David Siegel M.D., F.A.A.P., is a board-certified pediatrician from the New York metropolitan 

area. After earning his bachelor’s degree in biological sciences from the State University of New 

York at Stony Brook, he attended medical school at New York Medical College and completed 

his pediatric residency at the Montefiore Hospital of the Albert Einstein School of Medicine. He 

has had a multi-faceted career, spanning 30 years as a clinician, educator, and administrator in 

academic and community-based settings. As a clinician, he worked in the outpatient, 

emergency, and inpatient settings. As an educator/administrator, he became an ambulatory 

attending physician at the Children’s National Medical Center immediately following completion 

of his residency program; he then had a major role in the development and management of a new 

pediatric residency program at INOVA Fairfax Hospital for Children as the associate residency 

director and was the inpatient director at Connecticut Children’s Hospital. Following the events 

of September 11, 2001, while working in the emergency department at the Children’s National 

Medical Center, he initiated and managed the development of a pediatric preparedness training 

program, which dealt with the medical consequences of weapons of mass destruction, conducted 

through a grant from HRSA. Dr. Siegel joined the NICHD in October 2007 and, in addition to 

his functions as a medical officer, will be the Institute’s program director for Chemical, 

Biological, Radiological/Nuclear, and Explosive Incidents. 

Perdita Taylor-Zapata, M.D., is a board-certified pediatrician from the Washington D.C. area. 

She graduated from Howard University Medical School in 1994 and completed her pediatric 

residency training at the Children’s National Medical Center. After residency, she started 

working at the NIH as a clinic physician in the Pediatric HIV Working Group of the NCI, where 

she spent seven years taking care of the outpatient and inpatient medical needs of the HIVpositive pediatric patients enrolled in phase 1 and 2 clinical treatment trials. She was also 

involved in medical research, writing parts of clinical protocols and conducting retrospective and 

prospective research projects. As her career developed while at NCI, she became interested in 

the use, side effects, and toxicity profiles of medications used in children; in 2004, she published 

a paper in Pediatrics on lipodystrophy in HIV-infected children. Dr. Taylor-Zapata joined the 

OPPB in August 2004. She is now a medical officer working with a team of experts responsible 

for the implementation of BPCA activities. 

Anne Zajicek, M.D., is a board-certified pediatrician and pediatric clinical pharmacologist. 

After earning her bachelor’s degree in pharmacy from Duquesne University in 1982, Dr. Zajicek 

went on to obtain her doctorate in pharmacy from the State University of New York at Buffalo in 

1985. Dr. Zajicek then completed a postdoctoral fellowship in the Department of Pharmaceutics 

of St. Jude Children’s Research Hospital in 1987. From 1987 to 1991, she was an assistant 

professor at the University of Colorado School of Pharmacy and a clinical pharmacist at National 

Jewish Hospital and Research Center. In 1991, she entered medical school at the University of 

Pittsburgh. In 1998, she completed a pediatrics residency at the Children’s Hospital of 

Pittsburgh. Dr. Zajicek continued her training as a pediatric clinical pharmacology fellow at 

Stanford University, and she later joined the FDA in the Office of Clinical Pharmacology and 

Biopharmaceutics. In August 2003, she joined the NICHD as a pediatric medical officer and is 

currently the project officer for the BPCA Coordinating Center, for the BPCA-sponsored study 

of pharmacokinetics and pharmacodynamics of sodium nitroprusside in pediatric subjects, and 

for multiple BPCA-sponsored pediatric oncology studies. Dr. Zajicek is also the program officer 

for the OPRU Network. 

Appendices-2 
APPENDIX B: BEST PHARMACEUTICALS 

FOR CHILDREN ACT (BPCA) STUDIES 

STUDIES CONDUCTED THROUGH CONTRACTS/GRANTS FROM THE NICHD

Site Drug/Indication Study Type 

Washington 

University, St. Louis 

Baclofen for treatment of 

spasticity in children with 

cerebral palsy 

Chart review, 

Phase I Pharmacokinetics and 

Pharmacodynamics study 

Phase II and III dosing, safety, and efficacy 

studies 

Case Western 

Reserve University 

Lithium for the treatment of 

pediatric mania 

Phase I—Pharmacokinetics study; 

Phase II—8-week, randomized, placebocontrolled, double-blind study 

Children’s National 

Medical Center 

Lorazepam for the treatment of 

status epilepticus 

Phase I—Pharmacokinetics study 

Case Western 

Reserve University 

Lorazepam for the sedation of 

children on respirators in an 

intensive care unit 

Randomized double-blind active comparator 

Duke University and 

Stanford University 

Nitroprusside for the control of 

blood pressure 

Randomized double-blind parallel group 

Duke University Meropenem for intra-abdominal 

infections in neonates 

Phase I and II—Pharmacokinetics and safety 

study 

CROSS-DEPARTMENT AND CROSS-NIH STUDIES

Drug(s) Details Organization Study Type 

Ketamine Evaluate the scientific and safety 

concerns about its use as an 

anesthetic in children; initiated 

September 2004 

National Center for 

Toxicological Research, 

FDA 

Preclinical toxicology 

studies in primates 

Vincristine and 

Dactinomycin 

Evaluate safety and efficacy of 

treatment of malignancies in 

children; initiated September 

2004 

NCI Children’s Oncology 

Group 

Data collection and 

pharmacokinetic 

studies 

Hydroxyurea Determine the safety and efficacy 

of use in children with sickle-cell 

disease; initiated July 2005 

National Heart, Lung, and 

Blood Institute 

Phase III clinical trial 

Methotrexate Evaluate related neurotoxicity; 

initiated August 2005 

NCI Children’s Oncology 

Group 

Randomized 2x2 

factorial design 

Methylphenidate Evaluate genetic toxicity in mice 

and monkeys to enable the 

conduct of a safety assessment in 

humans; initiated August 2005 

National Center for 

Toxicological Research, 

FDA 

Pre-clinical studies in 

mice and monkeys 

Appendices-3 
Drug(s) Details Organization Study Type 

Methylphenidate 

and Adderal® 

Evaluate the effects on specific 

chromosomal damage endpoints 

in lymphocytes of children 

diagnosed with ADHD; initiated 

August 2005 

National Institute of 

Environmental Health 

Sciences (Through Duke 

University) 

Longitudinal 

observational study 

of pediatric ADHD 

patients 

Daunomycin Determine pharmacokinetics in 

children; initiated September 

2005 

NCI Children's Oncology 

Group 

Pharmacokinetic 

studies 

(Reference: http://bpca.nichd.nih.gov/clinical/studies/index.cfm) 

Appendices-4 
APPENDIX C: BPCA DRUG PRIORITIZATION LIST 

This list includes drugs which have been prioritized and published in the Federal Register since 

the implementation of BPCA. Once a drug is selected for consideration for study in children, the 

Branch works with the FDA and the pharmacoepidemiology database to determine feasibility of 

a potential clinical study. In some instances, it has not been possible to reach agreement among 

pediatric experts about endpoints for the studies. In other instances, the FDA indicated ongoing 

development of drugs that seem to offer substantial benefit over the drug originally considered 

for study. Finally, in some instances, concerns about toxicity suggested the need to develop 

animal studies before the human studies were designed. 

2003 

• Ampicillin/Sulbactam 

• Azithromycin 

• Baclofen 

• Bumetanide 

• Diazoxide 

• Dobutamine 

• Dopamine 

• Furosemide 

• Heparin 

• Isofluorane 

• Lindane 

• Lithium 

• Lorazepam 

• Meropenem 

• Metoclopramide 

• Piperacillin/Tazobactam 

• Promethazine 

• Rifampin 

• Sodium nitroprusside 

• Spironolactone 

2004 

• Ampicillin 

• Buproprion 

• Dactinomycin 

• Ketamine 

• Metolazone 

• Morphine 

• Vincristine 

2005 

• Acyclovir 

• Clonidine 

• Cyclosporine 

• Dexrazoxane 

• Eletriptan 

• Ethambutol 

• Flecainide 

• Griseofulvin 

• Hydrochlorothiazide 

• Hydrocortisone valerate 

• Hydroxychloroquine 

• Hydroxyurea 

• Ivermectin 

• Methadone 

• Methylphenidate 

• Sevelamer 

• Zonisamide 

2006 

• Albendazole 

• Amantidine 

• Bumetanide 

• Clonidine 

• Daunomycin 

• Furosemide guanfacine 

• Methotrexate 

• Mebendazole 

• Pralidoxime 

• Rimantadine 

Appendices-5 
APPENDIX D: BRANCH-SUPPORTED MEETINGS, 

FISCAL YEAR 2004 THROUGH FISCAL YEAR 2007 

• Efficacy versus Safety: Study Design Issues; Rockville, Maryland; February 20, 2004 

• Newborn Drug Development Initiative (NDDI) Meeting; Baltimore, Maryland; March 29-30, 

2004 

• Preclinical Models and Pediatrics Workshop; Rockville, Maryland; October 28, 2004 

• Consent Issues in Pediatric Clinical Trials; Rockville, Maryland; November 9, 2004 

• Neuroprotective Agents Conference; Monterey, California; November 14–19, 2004 

• Improving Pediatric Therapeutics through the BPCA; Washington, D.C.; May 16, 2005 

• Pediatric Hypertension Workshop (Part I); Rockville, Maryland; June 17, 2005 

• Conditions in Children Report Review; Rockville, Maryland; September 20, 2005 

• Medication in Children Report Review; Rockville, Maryland; September 28, 2005 

• Meeting on Parental Permission; Rockville, Maryland; November 4, 2005 

• BPCA Drug List Prioritization Annual Meeting; Bethesda, Maryland; November 8-9, 2005 

• Pediatric Formulation Initiative Working Meeting; Bethesda, Maryland; December 6-7, 2005 

• Emergency Research in Children: Ethical, Regulatory, and Clinical Challenges; Bethesda, 

Maryland; January 12-13, 2006 

• Global Consortium on Pediatric Pharmacology Meeting (held in conjunction with the 

American Society of Clinical Pharmacology and Therapeutics); Baltimore, Maryland; 

March 6, 2006 

• Society for Gynecologic Investigation Mini-Symposium; Toronto, Ontario, Canada; 

March 23, 2006 

• Pediatric Hypertension Workshop (Part 2); Bethesda, Maryland; April 7, 2006 

• 2nd Annual Summer Institute in Maternal-Fetal Pharmacology; Denver, Colorado; 

July 23-29, 2006 

• Meeting on the Waiver of Informed Consent—Community Involvement; Bethesda, Maryland; 

September 20, 2006 

• BPCA Drug List Prioritization Annual Meeting; Bethesda, Maryland; December 5-6, 2006 

• OPRU/PPRU Networks Meeting; Rockville, Maryland; July 19-20, 2007 

• 3rd Annual Maternal-Fetal Summer Institute and 3rd Annual Reproductive and Perinatal 

Epidemiology Institute; Montreal Quebec, Canada; July 29-August 4, 2007 

• Methylphenidate Scientific Discussion Meeting; Rockville, Maryland; September 24, 2007 

Appendices-6 
• Pediatric Infectious Diseases Meeting: Methicillin-Resistant Staph Aureus; Bethesda, 

Maryland; November 28-29, 2007 

• Meeting on Adolescent Health Literacy and Use of Over-the-Counter Medications, Bethesda, 

Maryland; December 6-7, 2007 

Appendices-7 
Appendices-8 

APPENDIX E: MEMBERS OF THE EXPERT PANEL 

Sandra Carson, M.D.* 

Division of Reproductive Endocrinology 

and Infertility 

Department of Obstetrics and Gynecology 

Women and Infant Hospital of Rhode Island 

Providence, RI 

George Daston, Ph.D. 

Miami Valley Laboratories 

Procter & Gamble, Inc. 

Cincinnati, OH 

Dave Flockhart, M.D., Ph.D. 

Chief, Division of Clinical Pharmacology 

Indiana University 

Indianapolis, IN 

Richard Gorman, M.D. 

Chair, Section on Clinical Pharmacology 

American Academy of Pediatrics 

Chicago, IL 

Michael Katz, M.D. 

Senior Vice President for Research and 

Global Programs 

March of Dimes Foundation 

White Plains, NY 

* NACHHD Council Member 

Sam Maldonado, M.D., M.P.H. 

Vice President, Pediatric Drug Development 

Johnson & Johnson Pharmaceutical 

Research and Development 

Raritan, NJ 

Brian Strom, M.D., M.P.H 

Associate Vice Dean 

School of Medicine 

University of Pennsylvania 

Philadelphia, PA 

Stan Szefler, M.D. 

Helen Wohlberg and Herman Lambert Chair 

in Pharmacokinetics; Co-Director, Weinberg 

Clinical Research Unit; Director, Pediatric 

Clinical Trials Center 

National Jewish Medical and Research 

Center 

Denver, CO 

Richard Weinshilboum, M.D. 

Professor, Molecular Pharmacology 

Mayo Clinic College of Medicine 

Rochester, MN 
APPENDIX F: BRANCH PUBLICATIONS, FISCAL YEAR 2004 

THROUGH FISCAL YEAR 2007 

(Branch staff names appear in bold below.) 

Attardi, B.J., Zeleznik, A., Simhan, H., Chiao, J.P., Mattison, D.R., & Caritis, S.N. (2007). 

Comparison of progesterone and glucocorticoid receptor binding and stimulation of gene 

expression by progesterone, 17-alpha hydroxyprogesterone caproate, and related progestins. 

Am J Obstet Gynecol, 197, e591-597. 

Berlin, C.M., LaKind, J.S., Fenton, S.E., Wang, R.Y., Bates, M.N., Brent, R.L., Condon, M., 

Crase, B.L., Dourson, M.L., Ettinger, A.S., Foos, B., Furst, P., Giacoia, G.P., Goldstein, 

D.A., Haynes, S.G., Hench, K.D., Kacew, S., Koren, G., Lawrence, R.A., Mason, A., 

McDiarmid, M.A., Moy, G., Needham, L.L., Paul, I.M., Pugh, L.C., Qian, Z., Salamone, L., 

Selevan, S.G., Sonawane, B., Tarzian, A.J., Rose Tully, M., & Uhl, K. (2005). Conclusions 

and recommendations of the expert panel: technical workshop on human milk surveillance 

and biomonitoring for environmental chemicals in the United States. J Toxicol Environ 

Health A, 68, 1825-1831. 

Frattarelli, D.A., Reed, M.D., Giacoia, G.P., & Aranda, J.V. (2004). Antifungals in systemic 

neonatal candidiasis. Drugs, 64, 949-968. 

Giacoia, G.P., Birenbaum, D.L., Sachs, H.C., & Mattison, D.R. (2006). The newborn drug 

development initiative. Pediatrics, 117, S1-S8. 

Giacoia, G.P., & Mattison, D.R. (2005). Newborns and drug studies: The NICHD/FDA 

newborn drug development initiative. Clin Ther, 27, 796-813. 

Giacoia, G.P., & Mattison, D.R. (2006). Selected proceedings of the NICHD/FDA newborn 

drug development initiative: Part II. Clin Ther, 28, 1337-1341. 

Giacoia, G.P., Taylor-Zapata, P., & Mattison, D. (2007). Need for appropriate formulations 

for children: The National Institute of Child Health and Human Development Pediatric 

Formulations Initiative, Part 1. International Journal of Pharmaceutical Compounding, 

11(1), 5-8. 

Giacoia, G.P., Taylor-Zapata, P., & Mattison, D. (2007). Need for appropriate formulations 

for children: The National Institute of Child Health and Human Development Pediatric 

Formulations Initiative, Part 2. International Journal of Pharmaceutical Compounding, 

11(3), 220-221. 

Jacobson-Kram, D., Mattison, D., Shelby, M., Slikker, W., Tice, R., & Witt, K. (2007). 

Methylphenidate and chromosome damage. Cancer Lett, Dec 3, [Epub ahead of print]. 

Koren, G., Kramer, M., & Mattison, D. (2007). The Summer Institutes in Maternal-Fetal 

Pharmacology: Building critical mass in a neglected area. J Obstet Gynaecol Can, 29, 544-

545. 

Mattison, D., & Zajicek, A. (2006). Gaps in knowledge in treating pregnant women. Gend Med, 

3: 169-182. 

Appendices-10 
McClure, E.M., Goldenberg, R.L., Brandes, N., Darmstadt, G.L., Wright, L.L., Armbruster, D., 

Biggar, R., Carpenter, J., Free, M.J., Mattison, D., Mathai, M., Moss, N., Mullany, L.C., 

Schrag, S., Tielsch, J., Tolosa, J., Wall, S.N., Schuchat, A., & Smine, A. (2007). The use of 

chlorhexidine to reduce maternal and neonatal mortality and morbidity in low-resource 

settings. Int J Gynaecol Obstet, 97, 89-94. 

Simhan, H.N., Chiao, J.P., Mattison, D.R., & Caritis, S.N. (2007). Human decidual cell Tolllike receptor signaling in response to endotoxin: The effect of progestins. Am J Obstet 

Gynecol, Oct 11, [Epub ahead of print]. 

Slikker, W., Jr., Young, J.F., Corley, R.A., Dorman, D.C., Conolly, R.B., Knudsen, T.B., Erstad, 

B.L., Luecke, R.H., Faustman, E.M., Timchalk, C., & Mattison, D.R. (2005). Improving 

predictive modeling in pediatric drug development: Pharmacokinetics, pharmacodynamics, 

and mechanistic modeling. Ann N Y Acad Sci, 1053, 505-518. 

Taylor-Zapata, P., & Mattison, D.R. (2007). Making progress for how medicines are used in 

children. Arch Pediatr Adolesc Med, 161, 916; author reply, 916-917. 

Ward, R.M., Benitz, W.E., Benjamin, D.K., Jr., Blackmon, L., Giacoia, G.P., Hudak, M., Lasky, 

T., Rodriguez, W., & Selen, A. (2006). Criteria supporting the study of drugs in the newborn. 

Clin Ther, 28, 1385-1398. 

Zajicek, A., & Giacoia, G.P. (2007). Obstetric clinical pharmacology: Coming of age. Clin 

Pharmacol Ther, 81, 481-482. 

Zhang, S., Mada, S.R., Mattison, D., Caritis, S., & Venkataramanan, R. (2007). Development 

and validation of a high-performance liquid chromatography-mass spectrometric assay for 

the determination of 17alpha-hydroxyprogesterone caproate (17-OHPC) in human plasma. J 

Chromatogr B Analyt Technol Biomed Life Sci, 856, 141-147. 

Zito, J.M., Safer, D.J., Valluri, S., Gardner, J.F., Korelitz, J.J., & Mattison, D.R. (2007). 

Psychotherapeutic medication prevalence in Medicaid-insured preschoolers. J Child Adolesc 

Psychopharmacol, 17, 195-203. 

Appendices-11