Pregnancy profoundly impacts normal physiology. When combined with the growth of the developing fetus and placenta, these changes result in multiple alterations in drug absorption, distribution, metabolism, and elimination. In this context, physiology-based pharmacokinetics modeling provides a powerful tool that can anticipate altered pharmacokinetics in pregnant women and predict maternal and fetal drug exposure in clinical scenarios that are untested or untestable, thereby contributing to an evidence-based approach to pharmacotherapy in pregnant patients. Although concerns about fetal safety have historically limited pharmacokinetic studies, many medications are clinically indicated for various maternal or fetal conditions and need further study.

Abstract. Although electroencephalography (EEG) is used to assess neonatal pain in research settings, EEG assessments have not been sufficiently characterized for use as end points to assess the efficacy of analgesics in regulatory-endorsed, industry-sponsored trials. We aimed to identify all studies conducted in neonates with EEG recordings during acute somatic nociceptive skin-breaking procedures, and to create a network of authors who will be invited to contribute their individual participant data (IPD) to an IPD meta-analysis to establish the validity, reliability, and clinical interpretability of an EEG-based neonatal pain measure. To identify literature, we searched MEDLINE, Embase, CINAHL, Web of Science, Scopus, Google Scholar, ClinicalTrials.gov, and the WHO ICTRP from database inception to July 2, 2025. Eligible studies were primary empirical studies that included neonates with EEG recordings during acute skin-breaking procedures. We identified 55 studies across 11 countries. Heel lance was the most common painful procedure; others included venipuncture, immunization, and lumbar puncture. The impact of 12 analgesic interventions has been studied to date, mostly nonpharmacological interventions. Individual-electrode EEG is more common than EEG caps. We noted relatively high data loss due to EEG data-quality concerns. A wide range of non-EEG pain-relevant measures have been recorded alongside EEG (eg, behavior, vital signs). Coauthorship network analysis highlighted that authors commonly work within discrete authorship hubs, with limited coauthorship across hubs. The predominance of studies was from European and American institutions, which limits generalizability. We conclude that sufficient data are available to undertake an IPD meta-analysis.

There are several major challenges limiting our ability to test analgesic efficacy for treatment of neonatal pain, and progress in analgesic drug studies in neonates has stalled. One significant issue is the reliance of clinical pain assessments on traditional behavioural and vital signs-based measures and the exclusion of novel brain-based biomarkers. In this review protocol, we outline our strategy to assess the reliability, validity, and interpretability of an electroencephalography (EEG)-based response biomarker for assessment of acute somatic nociceptive pain in neonates. To standardise EEG analysis and generate the outcome of interest, we will perform an individual participant data (IPD) meta-analysis using data from neonates aged 34–44-week postmenstrual age that have had EEG recorded during acute somatic nociceptive skin-breaking procedures. Relevant data from both published and grey literature will be identified by searching six databases (MEDLINE, Embase, CINAHL, Web of Science, Scopus, Google Scholar), two clinical trial registry platforms (ClinicalTrials.gov, WHO ICTRP), and by consulting expert opinion. We will assess availability bias, data accuracy, and data quality by cross-referencing provided data with data descriptions in the literature, identifying duplicates and nonsensical values, and extracting quality control metrics. Data will be synthesised via a two-stage IPD meta-analysis using a random effects modelling approach grouped by site. Reliability (inter- and intra-rater) outcomes will be measured as Gwet’s AC1 coefficient. Validity (known-groups and known-stimuli) outcomes will be measured as EEG response magnitude differences between clinically meaningfully different stimuli. Interpretability will be addressed by providing normative values, in both original and standardised units. The purpose of this study is to establish the reliability, validity, and interpretability of a specific EEG-based response biomarker for assessing acute somatic nociceptive pain in neonates. It will provide an overview of available data and how EEG is being used globally to assess acute neonatal pain. If sufficient IPD are made available and the outcome is reliable, valid, and interpretable, this work will support the use of EEG-based outcome measures as primary endpoints in clinical trials assessing analgesic efficacy in neonates. Systematic review registration: The protocol was registered with PROSPERO on 14 July 2023: CRD42023444809.

To support informed decisions on drug registration and prescription, clinical trials need tools to assess the efficacy and safety signals related to a given therapeutic intervention. Standardized assessment facilitates reproducibility of results. Furthermore, it enables weighted comparison between different interventions, instrumental to facilitate shared decisions. When focused on adverse events in clinical trials, tools are needed to assess seriousness, causality and severity. As part of such a toolbox, the international Neonatal Consortium (INC) developed a first version of the neonatal adverse event severity scale (NAESS). This version underwent subsequent validation in retro-and prospective trials to assess its applicability and impact on the inter-observer variability. Regulators, sponsors and academic researchers also reported on the use of the NAESS in regulatory documents, trial protocols and study reports. In this paper, we aim to report on the trajectory, current status and impact of the NAESS score, on how stakeholders within INC assess its relevance, and on perspectives to further develop this tool.

Background Clinical and analytical information on laboratory data of neonates in scientific publications is sparse and incomplete. Furthermore, interpreting neonatal laboratory data can be complex due to their time-dependent and developmental physiology, and paucity of well-established age-appropriate reference ranges for neonates. This study aims to develop publication recommendations to report laboratory data of neonates to enhance the quality of these data in research and clinical care. Methods A modified Delphi approach was used to develop recommendations in cooperation with the International Neonatal Consortium. A Core Group, including different stakeholders, was responsible for developing the recommendations, in collaboration with a Reflection Group, responsible for providing additional input. Results The recommendations were classified into three categories: ‘Clinical Characteristics’, ‘Bio-analytical Information’ and ‘Data-analytical Information’. These were each divided into ‘Core Data’ (always to be reported) and ‘Supplemental Considerations’ (to be reported when considered relevant to the study). Conclusion Our recommendations provide guidance on standardization of neonatal laboratory data in publications. This will enhance the comparison, replication, and application of study results in research initiatives and clinical practice. Furthermore, these recommendations also serve as foundational work to develop reference ranges for neonatal laboratory values by standardizing the quality of information needed for such efforts. Impact Standardized reporting of neonatal laboratory data in scientific publications will enhance the comparison, replication, and application of study results in research initiatives and clinical practice, as well as improve reporting to regulatory agencies. To integrate multistakeholder perspectives, a modified Delphi approach was used to develop publication recommendations which strengthens the applicability of the recommendations. Implementation of standardization will likely improve the overall quality of neonatal clinical research and neonatal healthcare. In addition, these recommendations are foundational to develop reference ranges for neonatal laboratory values by standardizing the quality of information needed for such efforts.

Prescription drug use is prevalent during pregnancy, yet there is limited knowledge about maternal-fetal safety and efficacy of this drug use because pregnant individuals have historically been excluded from clinical trials. Underrepresentation has resulted in a lack of data available to estimate or predict fetal drug exposure. Approaches to study fetal drug pharmacology are limited and must be evaluated for feasibility and accuracy. Anatomic and physiological changes throughout pregnancy fluctuate based on gestational age and can affect drug pharmacokinetics (PK) for both mother and fetus. Drug concentrations have been studied throughout different stages of gestation and at or following delivery in tissue and fluid biospecimens. Sampling amniotic fluid, umbilical cord blood, placental tissue, meconium, umbilical cord tissue, and neonatal hair present surrogate options to quantify and characterize fetal drug exposure. These sampling methods can be applied to all therapeutics including small molecule drugs, large molecule drugs, conjugated nanoparticles, and chemical exposures. Alternative approaches to determine PK have been explored, including physiologically based PK modeling, in vitro methods, and traditional animal models. These alternative approaches along with convenience sampling of tissue or fluid biospecimens can address challenges in studying maternal-fetal pharmacology. In this narrative review, we 1) present an overview of the current understanding of maternal-fetal drug exposure; 2) discuss biospecimen-guided sampling design and methods for measuring fetal drug concentrations throughout gestation; and 3) propose methods for advancing pharmacology research in the maternal-fetal population.

Protection of children from medication toxicity and providing evidence of effectiveness have long been the goals of studies of drugs in infants, children and adolescents. Ideally, the first child studied with a newly approved medication will receive that drug in dosages based on well-controlled studies with well-studied appropriate formulations in similar aged patients with similar disorders that established efficacy similar to what was required in adults. With motivation to achieve what is best for children, we have come a long way, but the progress is incomplete.In the 1800's, the beginning of modern pharmacopeia's emerged in the U.S. and Europe.1 These specified how to create medications by pharmacists who were skilled chemists. In the U.S., the first pharmacopoeia was published in 1820 and this was supplemented by legally protected Patent Medicines that often made outrageous therapeutic claims. A single product, such as Dr. Roger's Syrup, might be labeled effective for everything from a viral URI to tuberculosis (consumption in those days).2 In reality the primary ingredient was often ethanol which was readily dispensed and contributed to abuse by alcoholic adults and caused toxicity in children. Even cocaine toothache drops could be purchased over the counter for treatment of children.After over 25 years of appeals to Congress, Dr. Harvey Wiley, Chief of the Department of Chemistry of the Bureau of Agriculture, achieved passage of the 1906 Pure Food and Drug Act (PFDA), known in Washington as Wiley's Act.3 Enactment of this law coincided with the publication of Upton Sinclair's description of the unsanitary conditions in the meat packing plants in Chicago in The Jungle which supported the inclusion of foods in this law. The PFDA required food to be unadulterated and free from “putrid” ingredients. Similar to today, there were a lot of disagreements within Congress about the need for this law and how to implement it. The PFDA, signed by President Theodore Roosevelt, prohibited manufacture, sale, or interstate transportation of adulterated, misbranded, poisonous, or deleterious foods, liquors, drugs, and medicines based on its label. Supporters of this law included women's groups interested in protecting children. SEC. 4. Specified “That the examinations of specimens of foods and drugs shall be made in the Bureau of Chemistry of the Department of Agriculture, or under the direction and supervision of such Bureau.” This Bureau was under the review of Harvey Wiley, PhD. SEC.6. provided, “That the term “drug,” as used in this Act, shall include all medicines and preparations recognized in the United States Pharmacopoeia (USP) or National Formulary for internal or external use, and any substance or mixture of substances intended to be used for the cure, mitigation, or prevention of disease of either man or other animals.” Violators could be fined up to $500 and imprisoned for up to 1 year. In SEC 8. The Fourth provision indicated a drug was misbranded, “If the package containing it or its label shall bear any statement, design, or device regarding the ingredients or the substances contained therein, which statement, design, or device shall be false or misleading in any particular”. Although this act initiated the power to evaluate the accuracy of the label for a drug undergoing interstate commerce, it did not establish the Food and Drug Administration (FDA), contrary to some descriptions of this act. That would come later. It also did not require pre-emptive inspections before marketing.Later came in the 1930's when the azo dye prontosil was found by Gerhard Domagk to be metabolized into a potent antibiotic, sulfanilamide, that could effectively treat streptococcus, pneumococcus and gonococcus.4,5 Sulfanilamide was considered a wonder drug that decreased mortality dramatically and is credited with saving Winston Churchill's life when he developed pneumonia. Unfortunately, sulfonamide was virtually insoluble in water and was formulated and dispensed only in tablet form. Children who could not swallow a tablet were not able to be treated until an astute chemist found that sulfanilamide could be dissolved in diethylene glycol. It was tested only for taste and was then sold by the Massengill company as Elixir of Sulfanilamide-Massengill. In particular, it was not tested by the Council of Pharmacy and Chemistry of the American Medical Association to determine its safety and the solution was unknown to the Food and Drug Association of the U. S. Department of Agriculture. Sales by traveling salesmen began in September 1937 and by the following month over seventy deaths were reported to the American Medical Association.6 Patients died with anuria after treatment with this new solution of sulfanilamide. One death even occurred after a patient changed from tablets to the elixir. In total over 100 deaths were attributed to the Elixir of Sulfanilamide-Massengill, and the majority were children. Findings at autopsy were all similar with hepatic and renal necrosis which could be duplicated in animals treated with diethylene glycol or the Elixir of Sulfanilamide, but not by treatment with sulfanilamide.7 Geiling and Canon were assisted in these studies by a young pharmacology trainee, Frances Oldam Kelsey, who would play a major role in the next major phase of FDA regulations.4Diethylene glycol was already known to be toxic, but the only legal power to remove the elixir from the market was the 1906 Pure Food and Drug Act that made it misbranded, because an “elixir” was considered to be an ethanolic solution.8 As pointed out in a report by the Secretary of the Department of Agriculture, “Had the product been called a “solution,” rather than an “elixir,” no charge of violating the law could have been brought.”9 Dr. S. E. Massengill testified, “I have broken no laws” and was fined $16,500, but Harold Watson, the formulation chemist committed suicide.10It was clear that more stringent controls on pharmaceuticals were needed. The Federal Food, Drug and Cosmetic Act (FDCA), P.L. 75–717, was approved June 25, 1938.11 This law established quality standards for food, drugs, medical devices, and cosmetics manufactured and sold in the United States to be established before they undergo interstate commerce. The U.S. Food Drug and Cosmetic agency now assumed prospective regulatory authority for the first time. Oversight and enforcement of these standards were vested in the Secretary of Health and Human Services. Several provisions described how this oversight should be carried out to protect patents while insuring the products were safe for their intended use in patients. Many more regulations and laws followed to strengthen consumer protection in the use of medications.12In 1962, similar to discussions today, Senators Kefauver and Harris were conducting hearings concerning the high costs of drugs. At the same time, a severe congenital malformation syndrome was occurring in many countries, but primarily in Europe with phocomelia (seal like limbs), along with malformations of the ears, heart and intestinal tract. Dr. Helen Taussig who spoke fluent German traveled to Europe, investigated these cases, and wrote a thorough description of these disorders.13,14 Thalidomide was being marketed in 46 countries and sold over the counter, although that was later changed to requiring a prescription, due to a polyneuritis.In the U.S. Richardson-Merrell Pharmaceuticals had applied for FDA approval of thalidomide in 1960 when companies were allowed to sell drugs 60 days after submitting their request to the FDA if they showed that their drugs were safe as long as the FDA did not object.15 The company had distributed 20,000 tablets to physicians for research purposes. Dr. Frances Kelsey, who had trained in pharmacology and medicine, was one of 7 review officers at the time. She was assigned thalidomide for review. Dr. Kelsey had read a British study of neurological side effects and found that there were limited data backing up the company's claims of safety and even some falsified reports. Astute pediatricians in Germany presented cases at medical conferences and suggested a relationship between the multiple malformation syndrome and a new sedative medication often taken during pregnancy, Distaval, also known as thalidomide in the United States. Despite threats of lawsuits, Dr. Kelsey refused to approve it without more data about the outcomes from the treatment of pregnant women in the U.S. with the tablets distributed for research.Confirmation that the multi-malformation syndrome involving flipper-like limbs was caused by thalidomide and the limited protection by current laws led to the next phase of drug regulations. Kefauver and Harris who had been trying to strengthen FDA regulations pivoted their hearings and amended the 1938 FDCA to require both safety and efficacy be demonstrated before new drugs could be marketed in the U.S.16 Implementation of these Kefauver-Harris Amendments in 1962 led to the usual requirement for 2 randomized controlled studies demonstrating safety and efficacy before approval of new drugs.In 1962, Dr. Kelsey was awarded the Distinguished Civilian Service Medal by President John F. Kennedy. In 2010, the FDA initiated the Frances O. Kelsey Award for Excellence and Courage in Protecting Public Health and selected Dr. Kelsey as the first recipient at age 96.17Implementation of the Kefauver-Harris Amendments improved the quality of new medications, but this benefit for adults did not extend equally to children. By 1968, Dr. Harry Shirkey, a leader in pediatric drug dosing pointed out that pediatric patients were abandoned from inclusion in the studies leading to approval of new medications by the 1962 amendments and described children as “Therapeutic Orphans”. 18 A few years later, Dr John Wilson evaluated the labels of 2000 approved medications in the 1973 Physicians' Desk Reference and determined that 78% lacked pediatric prescribing information in the label.19 Several reasons for not studying medications in the pediatric population were proposed, including: it is unethical to study children; studying children is too hard; pediatric studies are too expensive. Despite efforts to increase pediatric studies to provide reliable data for dosing, efficacy and safety, the review by Wilson in 1973 and again in 1999 showed no increase in pediatric labeling.19,20In 1970, the FDA contracted with the American Academy of Pediatrics to develop a framework for the study of drugs in the pediatric population. The responsibility for this work was delegated to the Committee on Drugs (COD) which was being chaired by Sumner Yaffe, MD, who was in the middle of the longest period of leadership (10 yr) of the COD. By 1974, the COD had written, “General Guidelines for the Evaluation of Drugs to be Approved for Use During Pregnancy and for Treatment of Infants and Children.” 21 This 40 page treatise included a broad range of topics from ethics to analytic techniques. Chapters described developmental changes in drug metabolism as well as pharmacologic changes during pregnancy. Ages for study were defined for neonates, infants and adolescents. Although this was very thorough and well written, it had little effect on the frequency of pediatric drug studies.A few years later in 1977, the COD published one of the strongest statements about the need to study drugs in pediatrics, “Guidelines for the Ethical Conduct of Studies to Evaluate Drugs in Pediatric Populations.”22 “The Committee believes that it is unethical to adhere to a system which forces physicians to use therapeutic agents in an uncontrolled experimental situation virtually every time they prescribe for children. Furthermore, it is not only ethical but also imperative that new drugs to be used in children be studied in children under controlled circumstances so the benefits of therapeutic advances will become available to all who may need them.”In 1979, the FDA implemented a requirement that medication labels must contain a “pediatric use” section to describe how to use the medication to treat pediatric patients. The main result was the inclusion in the label that, “Safety and effectiveness in pediatric patients have not been established.” Overall, this effort was relatively ineffective.The continued lack of pediatric prescribing information in medication labels led the FDA to enact the 1994 Final Pediatric Rule which requested pediatric study and labeling if the drug was known to be used widely in pediatrics.23 One of the major provisions was allowing extrapolation of efficacy from adults to children without additional study if the disease process was similar in both populations. This would reduce expenses and duration of studies leading to labeling. The Rule also allowed labeling to be based solely on published randomized, well-controlled trials that met the standards of the FDA. Unfortunately, 77% of the changes submitted were inadequate to increase pediatric labeling and led instead to the familiar disclaimer, “Safety and effectiveness in pediatric patients have not been established.” To avoid delaying new treatments for adults, the FDA requested post marketing studies in pediatrics, but of 71 studies requested by 1991, only 11 studies were completed by 1997.24 Inclusion of pediatric prescribing information in the label of newly approved drugs, decreased from 9/17 (56%) in 1991 to 6/30 (20%) in 1998. Off-label prescribing remained the predominant basis for pediatric therapy.The FDA began to explore legislative solutions to create incentives for pediatric studies similar to what they had done for orphan and generic drugs in the form of market exclusivity. Market exclusivity is protection from competition provided by the FDA for a specific use of a new drug (new molecular entity) which may run during patent life. (Patent protection is completely separate protection provided by the Patent Trade Office and lasts 20 years.) Because the market for pediatric indications was quite small, the FDA considered applying market exclusivity for all uses of a new molecular entity not just for the pediatric indication. Questions arose about how much exclusivity would incentivize companies to undertake pediatric studies and what types of studies would provide optimal pediatric benefit. This led to the FDA Modernization Act of 1997 establishing Pediatric Exclusivity which differed from existing market exclusivity by extending existing market protection for an extra 6 months for all formulations and all uses of the active moiety.25The FDA Modernization Act of 1997 (FDAMA) was bipartisan legislation signed by President Clinton on November 21, 1997, intended to increase the study and labeling of drugs in the pediatric population. A Guidance indicating how to qualify for exclusivity was published in July, 1998. A drug could qualify for this exclusivity if “additional pediatric information may produce health benefits in the pediatric population”, a relatively low bar. This voluntary process required that the studies must conform to the FDA's Written Request (WR) that outlined the studies needed and they had to be completed before current market exclusivity expired. The WR could specify the pediatric population(s) by age and numbers to be studied as well as what indications to be studied. For some drugs, the pediatric indications were completely different from the indications in adults. FDAMA would sunset in 5 years unless it was renewed.FDAMA was essentially an experiment to increase pediatric studies and labeling. In the FDAMA Evaluation on September 1, 2001, a little over 3 years after its implementation, the FDA had issued 157 WRs for 332 pediatrics studies, awarded exclusivity to 25 products leading to 12 pediatric label changes.24 Many more studies and label changes were pending at the time of the 2001 report. “In general, the pediatric exclusivity provision has done more to generate clinical studies and useful prescribing information for the pediatric population than any other regulatory or legislative process to date.”24FDAMA was considered a success, but it came at a cost. According to Pharmacy Times, a pharmaceutical trade periodical, 6-month sales in 1997 for “block-buster” drugs ranged from over $402 Million for Augmentin to over $1.1 Billion for omeprazole (issue no longer available). Even noting that these figures are for sales, not profits, it was clear that added profits could easily pay for pediatric studies, estimated at $5-10 Million/study. But this did not apply to all drugs receiving PEDIATRIC EXCLUSIVITY. Nine of 33 drugs receiving exclusivity were not listed in the top 200 for sales. For some of these the costs of the pediatric studies likely exceeded sales.If FDAMA was considered the carrot for pediatric studies, the 1998 Final Rule was considered the stick. The 1998 Final Rule was proposed on 8/15/1997 and approved on 12/2/1998 to fill the gaps that the voluntary law, FDAMA, would leave.26 This Rule, written by the FDA, may require studies of new drugs if: 1) they provide a significant benefit over existing labeled therapies for a relevant pediatric population; 2) the absence of labeling could pose a significant risk to pediatric patients; 3) they are indicated for a condition in which few products are labeled for pediatric use. The 1998 Final Rule included the provision from the 1994 Final Rule that efficacy could be extrapolated to children if the disease is sufficiently similar in children and adults. Studies could be limited to dose, kinetics and safety. Each relevant age group had to be studied, which represented a big gain for newborns. It even provided that new formulations might be required which was often a pediatric challenge for drugs developed as tablets or capsules for adults. Waivers were possible if: a new formulation was required and could not be developed; if the drug was not an improvement over existing therapy; if it was unsafe for pediatric patients; and if study was impractical because of small pediatric populations.Approval of the 1998 Final Rule was followed quickly by lawsuits questioning the FDA's authority to require companies to conduct studies. On 10/17/2002, Judge Henry Kennedy in the District, wrote: “The Pediatric Rule may well be a better policy tool than the one enacted by Congress; it might reflect the most thoughtful, reasoned, balanced solution to a vexing public health problem. The issue here is not the Rule's wisdom. The issue is the Rule's statutory authority, and it is this that the court finds lacking.”27 The 1998 Final Rule was overturned, but Congress was coming to the rescue of pediatric studies. The next year in 12/2003, Congress passed the Pediatric Research Equity Act (PREA)28 reinstating almost all of the provisions of the 1998 Final Rule, but the differences from the voluntary process leading to Pediatric Exclusivity that had been renewed in 2002 as the Best Pharmaceuticals for Children Act (BPCA)29 need to be noted. PREA could only require pediatric studies of the indication being proposed for adults. But PREA maintained the requirement for studies “if they are likely to provide a health benefit” to children.BPCA reauthorized the 6-month exclusivity incentive for studies that fulfill the FDA WR before current market exclusivity expires. It added neonates as a special population needing study based on the number of studies that continued to stop at a lower age limit of 6–12 months. It required racial and ethnic representation in studies and established the Office of Pediatric Therapeutics (OPT) in the Commissioner's office. Every award of exclusivity required a 1-year follow-up safety report to the FDA Pediatric Advisory Committee that was established by the OPT.Pediatric therapy often continued to utilize off-patent, older medications, including those whose market exclusivity had recently expired leaving them without an incentive for pediatric study. To increase the study of these generic, off-patent drugs, BPCA established a foundation at the NIH to contract for study of off-patent drugs. Initial efforts to fund this with contributions from sponsors were unsuccessful. Later support was appropriated by Congress, but never authorized. Collaborations between NIH and FDA determined which drugs were most in need of study and established a list of these annually. A new challenge developed when off-patent drugs considered for study were suddenly patented again for a new indication or formulation. Because the label belongs to the original innovator company that developed and obtained approval, but which may not still exist, the FDA and NIH developed a process to publish a proposed label in the Federal Register for comment before it was added to the generic medication. These efforts to increase study and labeling of off-patent medications had little effect initially.In 2010 the National Institute for Child Health and Development funded the Pediatric Trials Network (PTN) at Duke led by Dr. Danny Benjamin. In studies approved by the IRB and with parental permission, investigators could obtain 2–3 small volume blood samples from children being treated with unlabeled medications. The investigators could also collect scavenged samples of extra blood from the clinical laboratory. Using micro-analytic techniques and population pharmacokinetic designs, the investigators defined the pharmacokinetics for these drugs to combine with clinical evidence of safety and efficacy. As of 2/2022, the PTN had established 22 study sites in 44 states and 4 countries that had enrolled over 11,000 patients.(Personal communication with Dr. Danny Benjamin) They had carried out 44 studies in 18 therapeutic areas, published over 97 manuscripts and added pediatric prescribing information to 17 drug labels.The Pediatric Exclusivity provision has been included in subsequent renewals of the incentive program in BPCA as part of the Food and Drug Administration Act of 2007 (FDAA)30 and the Food and Drug Administration Safety and Innovation Act of 2012 (FDASIA).31 FDAA was broadened to include study of devices for pediatrics in 2007. The requirement for pediatric studies of new drugs in PREA which was first passed in 2003 was renewed in 2007 and 2012 as part of FDAA and FDASIA, respectively. BPCA and PREA were finally made permanent in 2012 and show that PREA is now the predominant impetus for pediatric studies. In the 25 years since passage of FDAMA, the requirements and incentives for pediatric studies have been a success producing 996 pediatric studies with 572 by PREA only, 162 by PREA and BPCA, 196 by BPCA only, 16 by BPCA, and 50 by the pediatric rule.32Unfortunately, neonates have not benefited to the same extent as other pediatric patient populations. Laughon et al pointed out in 2014, that only a small percentage (7%) of studies for pediatric exclusivity included neonates.33 More problematic is the finding that a review of over 446,000 NICU patients showed that of the 28 drugs studied in newborns for exclusivity 21 of these 28 were never or seldom (0.013%) used to treat neonatal patients. Participation in clinical trials of medications which are not used in this population violates basic ethical standards. Although neonatal studies are challenging, these critically ill patients remain therapeutic orphans.Since 1997, pediatric studies have increased to the point that many sponsors plan on pediatric studies early in their drug development program. This increase in pediatric studies generated many more pediatric investigators and study coordinators. Institutional Review Boards have developed experience and expertise in the review of pediatric studies. These expansions have been accompanied by an increase of pediatricians at the FDA to assist in the requested designs of pediatric studies. The experiment that began with the incentive program of FDAMA has been a success, but new efforts are needed to extend that success to neonates and maintain the increased study of drugs in pediatric patients. Members of the Pediatric Pharmacy Association (PPA) have unique knowledge of pediatric pharmacology that can support pediatric studies and help educate pediatricians. The American Academy of Pediatrics Section on Clinical Pharmacology and Therapeutics (SOCPT) would welcome input from members of the PPA through two different levels of participation. Members with a PharmD degree and board certification as Pediatric Pharmacy Specialists can become National Affiliate members with full voting rights and access to leadership roles within the Section. A PPA member just served as the President of the Executive Committee of the SOCPT and others have served on the executive committee of the section. PPA members who don't qualify for National Affiliate membership can still lend their expertise to the AAP as Section Affiliate members. Together, pediatricians and pharmacists can continue the progress in pediatric studies of medications so the first child treated with a new medication receives that medication based on thorough study of dosage, safety and effectiveness.

BACKGROUND:Numerous reports contend opioids can augment or inhibit malignancy. At present, there is no consensus on the risk or benefit posed by opioids on malignancy or chemotherapeutic activity. Distinguishing the consequences of opioid use from pain and its management is challenging. Additionally, opioid concentration data is often lacking in clinical studies. A scoping review approach inclusive of preclinical and clinical data will improve our understanding of the risk-benefit relationship concerning commonly prescribed opioids and cancer and cancer treatment. OBJECTIVE:The aim of the study is to map diverse studies spanning from preclinical to clinical regarding opioids with malignancy and its treatment. METHODS:This scoping review will use the Arksey six stages framework to (1) identify the research question; (2) identify relevant studies; (3) select studies meeting criteria; (4) extract and chart data; (5) collate, summarize, and report results; and (6) conduct expert consultation. An initial pilot study was undertaken to (1) parameterize the extent and scale of existing data for an evidence review, (2) identify key factors to be extracted in systematic charting efforts, and (3) assess opioid concentration as a variable for its relevance to the central hypothesis. Six databases will be searched with no filters: MEDLINE, Embase, CINAHL Complete, Cochrane Library, Biological Sciences Collection, and International Pharmaceutical Abstracts. Trial registries will include ClinicalTrials.gov, Cochrane CENTRAL, International Standard Randomised Controlled Trial Number Registry, European Union Clinical Trials Register, and World Health Organization International Clinical Trials Registry. Eligibility criteria will include preclinical and clinical study data on opioids effects on tumor growth or survival, or alteration on the antineoplastic activity of chemotherapeutics. We will chart data on (1) opioid concentration from human subjects with cancer, yielding a "physiologic range" to better interpret available preclinical data; (2) patterns of opioid exposure with disease and treatment-related patient outcomes; and (3) the influence of opioids on cancer cell survival, as well as opioid-related changes to cancer cell susceptibility for chemotherapeutics. RESULTS:This scoping review will present results in narrative forms as well as with the use of tables and diagrams. Initiated in February 2021 at the University of Utah, this protocol is anticipated to generate a scoping review by August 2023. The results of the scoping review will be disseminated through scientific conference proceedings and presentations, stakeholder meetings, and by publication in a peer-reviewed journal. CONCLUSIONS:The findings of this scoping review will provide a comprehensive description of the consequences of prescription opioids on malignancy and its treatment. By incorporating preclinical and clinical data, this scoping review will invite novel comparisons across study types that could inform new basic, translational, and clinical studies regarding risks and benefits of opioid use among patients with cancer. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID):PRR1-10.2196/38167.

This report updates previous CDC guidelines and recommendations on preferred prevention and treatment regimens regarding naturally occurring anthrax. Also provided are a wide range of alternative regimens to first-line antimicrobial drugs for use if patients have contraindications or intolerances or after a wide-area aerosol release of:Bacillus anthracis spores if resources become limited or a multidrug-resistant B. anthracis strain is used (Hendricks KA, Wright ME, Shadomy SV, et al.; Workgroup on Anthrax Clinical Guidelines. Centers for Disease Control and Prevention expert panel meetings on prevention and treatment of anthrax in adults. Emerg Infect Dis 2014;20:e130687; Meaney-Delman D, Rasmussen SA, Beigi RH, et al. Prophylaxis and treatment of anthrax in pregnant women. Obstet Gynecol 2013;122:885-900; Bradley JS, Peacock G, Krug SE, et al. Pediatric anthrax clinical management. Pediatrics 2014;133:e1411-36). Specifically, this report updates antimicrobial drug and antitoxin use for both postexposure prophylaxis (PEP) and treatment from these previous guidelines best practices and is based on systematic reviews of the literature regarding 1) in vitro antimicrobial drug activity against B. anthracis; 2) in vivo antimicrobial drug efficacy for PEP and treatment; 3) in vivo and human antitoxin efficacy for PEP, treatment, or both; and 4) human survival after antimicrobial drug PEP and treatment of localized anthrax, systemic anthrax, and anthrax meningitis.Changes from previous CDC guidelines and recommendations include an expanded list of alternative antimicrobial drugs to use when first-line antimicrobial drugs are contraindicated or not tolerated or after a bioterrorism event when first-line antimicrobial drugs are depleted or ineffective against a genetically engineered resistant:B. anthracis strain. In addition, these updated guidelines include new recommendations regarding special considerations for the diagnosis and treatment of anthrax meningitis, including comorbid, social, and clinical predictors of anthrax meningitis. The previously published CDC guidelines and recommendations described potentially beneficial critical care measures and clinical assessment tools and procedures for persons with anthrax, which have not changed and are not addressed in this update. In addition, no changes were made to the Advisory Committee on Immunization Practices recommendations for use of anthrax vaccine (Bower WA, Schiffer J, Atmar RL, et al. Use of anthrax vaccine in the United States: recommendations of the Advisory Committee on Immunization Practices, 2019. MMWR Recomm Rep 2019;68[No. RR-4]:1-14). The updated guidelines in this report can be used by health care providers to prevent and treat anthrax and guide emergency preparedness officials and planners as they develop and update plans for a wide-area aerosol release of B. anthracis.

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

Background Low levels of insulin-like growth factor-1 (IGF-1) protein in preterm human infants are associated with bronchopulmonary dysplasia (BPD). We used our preterm lamb model of BPD to determine (1) dosage of recombinant human (rh) IGF-1 bound to binding protein-3 (IGFBP-3) to reach infant physiologic plasma levels; and (2) whether repletion of plasma IGF-1 improves pulmonary and cardiovascular outcomes. Methods Group 1: normal, unventilated lambs from 128 days gestation through postnatal age 5 months defined normal plasma levels of IGF-1. Group 2: continuous infusion of rhIGF-1/rhIGFBP-3 (0.5, 1.5, or 4.5 mg/kg/day; n = 2) for 3 days in mechanically ventilated (MV) preterm lambs determined that 1.5 mg/kg/day dosage attained physiologic plasma IGF-1 concentration of ~125 ng/mL, which was infused in four more MV preterm lambs. Results Group 1: plasma IGF-1 protein increased from ~75 ng/mL at 128 days gestation to ~220 ng/L at 5 months. Group 2: pilot study of the optimal dosage (1.5 mg/kg/day rhIGF-1/rhIGFBP-3) in six MV preterm lambs significantly improved some pulmonary and cardiovascular outcomes ( p < 0.1) compared to six MV preterm controls. RhIGF-1/rhIGFBP-3 was not toxic to the liver, kidneys, or lungs. Conclusions Three days of continuous iv infusion of rhIGF-1/rhIGFBP-3 at 1.5 mg/kg/day improved some pulmonary and cardiovascular outcomes without toxicity. Impact Preterm birth is associated with rapid decreases in serum or plasma IGF-1 protein level. This decline adversely impacts the growth and development of the lung and cardiovascular system. For this pilot study, continuous infusion of optimal dosage of rhIGF-1/rhIGFBP-3 (1.5 mg/kg/day) to maintain physiologic plasma IGF-1 level of ~125 ng/mL during mechanical ventilation for 3 days statistically improved some structural and biochemical outcomes related to the alveolar formation that would favor improved gas exchange compared to vehicle-control. We conclude that 3 days of continuous iv infusion of rhIGF-1/rhIGFBP-3 improved some physiological, morphological, and biochemical outcomes, without toxicity, in mechanically ventilated preterm lambs.

Background: There are anecdotal reports on reversible QTc prolongation during therapeutic hypothermia (TH) for moderate to severe neonatal encephalopathy after asphyxia. As the QTc interval is a relevant biomarker for pharmacovigilance during medication development, a structured search and review on published neonatal QTc values to generate reference values is warranted to facilate medication development in this specific population. Methods: A structured search and literature assessment (PubMed, Embase, and Google Scholar) with ‘Newborn/Infant, QT and hypothermia’ was conducted (October 2021). Retrieved individual values were converted to QTc (Bazett) over postnatal age (day 1–7). Results: We retrieved 94 QTc intervals (during TH (n = 50, until day 3) or subsequent normothermia (n = 44, day 4–7)) in 33 neonates from 6 publications. The median (range) of QTc intervals during TH was 508 (430–678), and 410 (317–540) ms afterwards (difference 98 ms, or +28 ms/°C decrease). Four additional cohorts (without individual QTc intervals) confirmed the pattern and magnitude of the effect of body temperature on the QTc interval. Conclusions: We highlighted a relevant non-maturational covariate (°C dependent TH) and generated reference values for the QTc interval in this specific neonatal subpopulation. This knowledge on QTc during TH should be considered and integrated in neonatal medication development.

Objective Chronic lung disease of prematurity (CLDP) is a frequent complication of prematurity. We aimed to identify what clinicians believe are the most important factors determining the severity of CLDP in extremely preterm infants (<28 weeks gestational age) after discharge from the neonatal intensive care unit (NICU) through 12 months corrected age (CA), and to evaluate how these factors should be weighted for scoring, to develop a CLDP severity scale. Study design Clinicians completed a three-round online survey utilizing Delphi methodology. Clinicians rated the importance of various factors used to evaluate the severity of CLDP, from 0 (not at all important) to 10 (very important) for the period between discharge home from the NICU and 12 months CA. Fourteen factors were considered in Round 1; 13 in Rounds 2 and 3. The relative importance of factors was explored via a set of 16 single-profile tasks (i.e., hypothetical patient profiles with varying CLDP severity levels). Results Overall, 91 clinicians from 11 countries who were experienced in treating prematurity-related lung diseases completed Round 1; 88 completed Rounds 2 and 3. Based on Round 3, the most important factors in determining CLDP severity were mechanical ventilation (mean absolute importance rating, 8.89), supplemental oxygen >= 2 L/min (8.49), rehospitalizations (7.65), and supplemental oxygen <2 L/min (7.56). Single-profile tasks showed that supplemental oxygen had the greatest impact on profile classification. Conclusion The most important factors for clinicians assigning CLDP severity during infancy were mechanical ventilation, supplemental oxygen >= 2 L/min, and respiratory-related rehospitalizations.

Introduction: Graft survival in pediatric kidney transplant patients has increased significantly within the last three decades, correlating with the discovery and utilization of new immunosuppressants as well as improvements in patient care. Despite these developments in graft survival for patients, there is still improvement needed, particularly in long-term care in pediatric patients receiving grafts from deceased donor patients. Maintenance immunosuppressive therapies have narrow therapeutic indices and are associated with high inter-individual and intra-individual variability.Areas covered: In this review, we examine the impact of pharmacokinetic variability on renal transplantation and its association with age, genetic polymorphisms, drug-drug interactions, drug-disease interactions, renal insufficiency, route of administration, and branded versus generic drug formulation. Pharmacodynamics are outlined in terms of the mechanism of action for each immunosuppressant, potential adverse effects, and the utility of pharmacodynamic biomarkers.Expert opinion: Acquiring abetter quantitative understanding of immunosuppressant pharmacokinetics and pharmacodynamic components should help clinicians implement treatment regimens to maintain the balance between therapeutic efficacy and drug-related toxicity.

Initial trials of lung-targeted budesonide (0.25 mg/kg) in surfactant to prevent bronchopulmonary dysplasia (BPD) in premature infants have shown benefit; however, the optimal safe dose is unknown. Dose-escalation study of budesonide (0.025, 0.05, 0.10 mg/kg) in calfactatant in extremely low gestational age neonates (ELGANs) requiring intubation at 3−14 days. Tracheal aspirate (TA) cytokines, blood budesonide concentrations, and untargeted blood metabolomics were measured. Outcomes were compared with matched infants receiving surfactant in the Trial Of Late SURFactant (TOLSURF). Twenty-four infants with mean gestational age 25.0 weeks and 743 g birth weight requiring mechanical ventilation were enrolled at mean age 6 days. Budesonide was detected in the blood of all infants with a half-life of 3.4 h. Of 11 infants with elevated TA cytokine levels at baseline, treatment was associated with sustained decrease (mean 65%) at all three dosing levels. There were time- and dose-dependent decreases in blood cortisol concentrations and changes in total blood metabolites. Respiratory outcomes did not differ from the historic controls. Budesonide/surfactant had no clinical respiratory benefit at any dosing levels for intubated ELGANs. One-tenth the dose used in previous trials had minimal systemic metabolic effects and appeared effective for lung-targeted anti-inflammatory action.

To describe relationship between cord blood (representing fetal) myo-inositol concentrations and gestational age (GA) and to determine trends of blood concentrations in enterally and parenterally fed infants from birth to 70 days of age. Samples were collected in 281 fed or unfed infants born in 2005 and 2006. Myo-inositol concentrations were displayed in scatter plots and analyzed with linear regression models of natural log-transformed values. In 441 samples obtained from 281 infants, myo-inositol concentrations varied from nondetectable to 1494 μmol/L. Cord myo-inositol concentrations decreased an estimated 11.9% per week increase in GA. Postnatal myo-inositol concentrations decreased an estimated 14.3% per week increase in postmenstrual age (PMA) and were higher for enterally fed infants compared to unfed infants (51% increase for fed vs. unfed infants). Fetal myo-inositol concentrations decreased with increasing GA. Postnatal concentrations decreased with increasing PMA and were higher among enterally fed than unfed infants.

Background: Comprehensive measures to evaluate the effectiveness of medical interventions in extremely preterm infants are lacking. Although length of stay is used as an indicator of overall health among preterm infants in clinical studies, it is confounded by nonmedical factors (e.g. parental readiness and availability of home nursing support). Objectives: To develop the PREMature Infant Index (PREMII (TM)), an electronic content-valid clinician-reported outcome measure for assessing functional status of extremely preterm infants (<28 weeks gestational age) serially over time in the neonatal intensive care unit. We report the development stages of the PREMII, including suggestions for scoring. Methods: We developed the PREMII according to US Food and Drug Administration regulatory standards. Development included five stages: (1) literature review, (2) clinical expert interviews, (3) Delphi panel survey, (4) development of items/levels, and (5) cognitive interviews/usability testing. Scoring approaches were explored via an online clinician survey. Results: Key factors reflective of functional status were identified by physicians and nurses during development of the PREMII, as were levels within each factor to assess functional status. The resulting PREMII evaluates eight infant health factors: respiratory support, oxygen administration, apnea, bradycardia, desaturation, thermoregulation, feeding, and weight gain, each scored with three to six gradations. Factor levels are standardized on a 0-100 scale; resultant scores are 0-100. No usability issues were identified. The online clinician survey identified optimal scoring methods to capture functional status at a given time point. Conclusions: Our findings support the content validity and usability of the PREMII as a multifunction outcome measure to assess functional status over time in extremely preterm infants. Psychometric validation is ongoing.

Pharmacokinetic (PK) conflicts can arise between supportive care medications (SCM) and chemotherapy in children with hematologic malignancy (HM). In this retrospective study, medical records for children (28 days-18 years) diagnosed with HM and receiving an SCM antimicrobial were collected from a hospital network between 1 May 2000 and 31 December 2014. PK drug-gene associations were obtained from a curated pharmacogenomics database. Among 730 patients (median age of 7.5 (IQR 3.7-13.9) years), primarily diagnosed with lymphoid leukemia (52%), lymphoma (28%), or acute myeloid leukemia (16%), chemotherapy was administered in 2846 hospitalizations. SCM accounted for 90.5% (n = 448) of distinct drugs with 93% (n = 679) of children, receiving >= 5 different SCM/hospitalization. Same-day SCM/chemotherapeutic PK gene overlap occurred in 48.3% of hospitalizations and was associated with age (p = 0.026), number of SCM, HM subtype, surgery, and hematopoietic stem cell transplant (p < 0.0001). A high and variable SCM burden among children with HM receiving chemotherapy poses a risk for unanticipated PK conflicts.

The objective of this study was to evaluate the predictive performance of population models to predict renal clearance in newborns and infants. Pharmacokinetic (PK) data from eight drugs in 788 newborns and infants were used to evaluate the predictive performance of the population models based on postmenstrual age (PMA), postnatal age, gestational age, and body weight. For the PMA model, the average fold error for clearance (CL) predicted /CL observed was within a twofold range for each drug in all subgroups. For drugs with > 90% renal elimination, the prediction bias ranged from 0.7−1.3. For drugs with 60–80% renal elimination, the prediction bias ranged 0.6–2.0. Our results suggest that PMA‐based sigmoidal maximum effect (E max ) model, in combination with bodyweight‐based scaling and kidney function assessment, can be used in population PK (PopPK) modeling for drugs that are primarily eliminated via renal pathway to inform initial dose selection for newborns and infants with normal renal function in clinical trials.