Pediatric Drug Development Research Articles

Better Medicines for Children: Lessons Learnt and Share Learnings at the EFGCP Annual Paediatric Conferences.

For many years, the European Forum for Good Clinical Practice (EFGCP) Children Medicines Working Party has organised a Paediatric conference annually. In the past, this event was organised jointly with the European Medicines Agency who was used to host it, along with the Drug Information Association (DIA). This conference is the opportunity for all involved in paediatric drug development, i.e., regulators, HTA bodies, patients' representatives, academia and industry, to share learnings and raise awareness about new regulatory requirements of interest to optimise paediatric drug development. The theme of the 2021 conference was "Challenges and Solutions - the path forward" while in 2022 it focused on "Progress made and Continuing Challenges". Because of the COVID-19 pandemic these two conferences were organised virtually. However, this has not impacted the attendance and value of the conference, since because of a broad and attractive agenda there was a wide stakeholder participation, which provided a compendious overview of the leading issues to improve children's access to innovative medicines.

Pediatric-Specific Drug Loss Issue in Japan: Comparison of Pediatric Development Status Between Japan and the United States.

The lack of label information for the pediatric population has been a global issue, leading to the introduction of several countermeasures by major health authorities. Despite various efforts by Japanese health authorities, some drugs are approved only for adults in Japan, while the United States (US) label includes information on pediatric usage for the same drugs. This suggests a potential for pediatric-specific drug loss in Japan, where overall drug loss has recently become a major concern. In this study, we compared the pediatric usage status between Japan and the US, focusing on the indications approved in both countries. Of the 404 indications, 70 (17.3%) and 102 (25.2%) included pediatric usage in Japan and the US, respectively. The proportion of indications, including pediatric usage, was significantly higher in the US than in Japan (χ2 test, p < 0.001). Multivariate analysis of indications for pediatric usage in the US demonstrated that simultaneous development with adults (odds ratio (OR), 24.9; 95% confidence interval (CI), 6.79-91.1) and Japan-first development (OR, 31.5; 95% CI, 2.59-384) were significantly affecting the inclusion of pediatric usage in Japan. Our results suggest that there was pediatric-specific drug loss in Japan compared to that in the US. The multivariate analysis demonstrated that US-first development and non-simultaneous development had a negative impact on the inclusion of pediatric usage in Japan; however, pediatric assessment request was not a significant factor. Further frameworks to promote pediatric drug development should be introduced in Japan to address pediatric-specific drug loss issues.

Landscape of regulatory quantitative systems pharmacology submissions to the U.S. Food and Drug Administration: An update report.

The number of quantitative systems pharmacology (QSP) submissions to the U.S. Food and Drug Administration has continued to increase over the past decade. This report summarizes the landscape of QSP submissions as of December 2023. QSP was used to inform drug development across various therapeutic areas and throughout the drug development process of small molecular drugs and biologics and has facilitated dose finding, dose ranging, and dose optimization studies. Though the majority of QSP submissions (>66%) focused on drug effectiveness, QSP was also utilized to simulate drug safety including liver toxicity, risk of cytokine release syndrome (CRS), bone density, and others. This report also includes individual contexts of use from a handful of new drug applications (NDAs) and biologics license applications where QSP modeling was used to demonstrate the utility of QSP modeling in regulatory drug development. According to the models submitted in QSP submissions, an anonymous case was utilized to illustrate how QSP informed development of a bispecific monoclonal antibody with respect to CRS risk. QSP submissions for informing pediatric drug development were summarized along with highlights of a case in inborn errors of metabolism. Furthermore, simulations of response variability with QSP were described. In summary, QSP continues to play a role in informing drug development.

Investigating the effect of whey and casein proteins on drug solubility from a paediatric drug absorption perspective

Considering the predominantly milk-based diet of neonates and infants and their immature gastrointestinal digestion, milk proteins may affect drug behaviour and absorption in this population. Using in vitro models, this study investigated the impact of the representative milk proteins, whey and casein, on the solubility and permeation of the lipophilic model drugs spironolactone, clopidogrel and ritonavir. Drug solubility experiments revealed that the presence of milk proteins increased drug solubility. Next, permeation studies demonstrated that the same milk proteins reduced drug permeation across an artificial membrane. These results highlight the importance of the solubility-permeability interplay and indicate the effect of these proteins may be considered during (paediatric) drug development. Lastly, the findings underscore the importance of considering milk protein-drug interactions to optimize drug delivery strategies during (paediatric) drug development and especially for the youngest and most vulnerable part of this population.

Prediction of absolute bioavailability of medicines in children: based on predicted pediatric clearance from adults

Aim: The objective of this study was to evaluate the predictive performance of a proposed method to predict absolute bioavailability of medicines in children (infants to adolescents). Methods: From the literature, systemic and oral clearances as well as absolute bioavailability values for 15 medicines (28 observations across different age groups) from infants to adults were obtained. Systemic and oral clearances of these medicines in children were predicted using age-dependent exponent (ADE) allometric model using observed adult clearance values. Then using the predicted clearance values, absolute bioavailability was predicted in children. The predictive performance of the proposed method was evaluated by comparing the predicted absolute bioavailability of the studied drugs with the observed absolute bioavailability in children. Results: The results of the study indicated that the ADE model provided a good prediction of systemic and oral clearances in children from adult clearance values (89% and 82% observations within 0.5–1.5-fold prediction error, respectively). The predicted absolute bioavailability by the proposed method was within 0.5–1.5-fold prediction error for 93% observations. Conclusions: This study indicated that it was possible to estimate absolute bioavailability of medicines in children with acceptable accuracy (within 0.5–1.5-fold prediction error) by the proposed method. The estimated absolute bioavailability in children could be useful in designing a first-in-children dose during pediatric drug development.

Paediatric Drug Development in Japan: Current Status and Future Challenges.

Until around 2000, the number of medicinal products labelled for paediatric use was limited worldwide. Regulatory measures to promote paediatric drug development in the US and Europe and the establishment of an international guideline (ICH-E11) have led to an increase in the number of paediatric labels. In Japan, efforts have been made to promote the development of paediatric drugs. This study was aimed to examine whether these supportive efforts are successful in Japan. This study examined the number of new drugs approved for paediatric indications in Japan from 2006 to 2023, as well as the clinical data package, that is, characteristics of the approved paediatric drugs and paediatric clinical trials, and the percentage of extrapolation of adult data, in the most recent 9-year period. The number of paediatric drug approvals showed an increasing trend between 2006 and 2023 with some fluctuations. The proportion of drugs indicated for paediatric patients to the total number of approved drugs was about 30% until 2022, but increased to 48% in 2023. During the period from 2015 to 2023, simultaneous development in adults and children accounted for 59% (159/269) of paediatric development, but the complete extrapolation of adult data to paediatric populations has not been widely utilized (11.2%, 30/269). The number of paediatric drug approvals has shown an upward trend, suggesting that measures to promote the development of paediatric drugs may have been exerting a favourable effect in Japan. However, there is still a limited number of drugs that have additional indications for paediatric use. Appropriate development strategies, such as the extrapolation of adult data to paediatric populations, should be considered if scientifically justified.

Unleashing PBPK Modeling Potential in Pediatric Drug Development

Unleashing PBPK Modeling Potential in Pediatric Drug Development

Adherence, Adverse Events and Viral Control among Children and Adolescents with HIV in Zambia Switched to an Integrase Inhibitor Regimen.

Based on recent World Health Organization recommendations, there has been a large-scale transition in Sub-Saharan Africa to integrase inhibitor (II)-based antiretroviral therapy (ART) regimens. This study was conducted at an urban referral center in Lusaka, Zambia. This study included 297 children and adolescents with HIV (CAWH) on ART for one year prior to enrollment and followed for 1-4 years after enrollment. ART adherence, ART regimen, and viral load were assessed periodically. Structured interviews were conducted with a subset of 95 children to assess adherence barriers and side effects. Children on protease inhibitor (PI)-based regimens were more likely to report adherence problems than children taking II- or Efavirenz-based regimens (10% vs. 28%, p=0.03) and noted more days with missed doses (median 1 vs. 0, p=0.02). In interviews, the most common reasons given for poor adherence included bad medication taste, not being home when medications were due, and perceived side effects. The PI group was more likely to report that taste was a problem affecting adherence (22% vs. 4%, p=0.05) and headache as an ART side effect (17% vs. 4%, p=0.05). Switching from a PI- to an II-based regimen was associated with improved adherence (72% vs. 92%, p=0.01) and an undetectable viral load (67% vs. 78%). Switching CAWH from PI-based to II-based regimens has many advantages including superior side effect profiles, adherence, and viral suppression. PI taste aversion may be a significant contributor to pediatric adherence issues. Palatability should be considered in pediatric HIV drug development.

Pediatric Rare Diseases Development in the Pharmaceutical Industry: An International Consortium for Innovation and Quality in Pharmaceutical Development, Clinical Pharmacology Leadership Group-Pediatrics Working Group, Rare Diseases Subteam Whitepaper Examining the Current Landscape and Recommendations for the Future.

Many new opportunities surround rare pediatric disease drug development, thanks to key advances in regulatory thinking and in the scientific community. As rare disease drug development brings challenges to the developers in terms of limited understanding of natural history, heterogeneity in drug response, as well as difficulty recruiting patients in pivotal trials, there has never been a greater need for quantitative integration. To understand how International Consortium for Innovation and Quality in Pharmaceutical Development (IQ) member companies approach pediatric rare disease drug development, the rare pediatric subteam of the Clinical Pharmacology Leadership Group (CPLG) sponsored Pediatrics Working Group conducted a baseline survey to assess the four main pillars of this quantitative innovation, namely, biomarkers and surrogate end points, statistical methodologies, model-informed drug development, as well as public-private partnerships. The survey was administered by IQ and yielded 13 evaluable responders from represented companies. This article presents the key findings from this baseline identifying survey, highlighting the key blind spots, and providing insightful expert opinions to address those gaps. In summary, we call an urgent attention to the community on the opportunities to enhance integration and within-industry learnings from this analysis on aspects related to platform studies, end-to-end quantitative integration, and sharing of trial-level placebo data for better understanding of disease progression and more efficient trial designs. We collectively hope that these findings will stimulate discussion and debate around cross-industry sharing and collaboration to better delineate principles and further enhance the efficiency of rare pediatric disease drug development.

Advancing research and development of anti-infectives for children: A clinical development perspective

The HIV treatment landscape for adults has progressed dramatically in recent decades; however, paediatric populations continue to experience delayed and limited access to effective and safe antiretroviral therapy options. Despite current incentive programmes, formulation research and development and approved drug dosing for children have been limited, particularly for neonates (aged <4 wk). Regulatory approval of drug formulations and dosing in children may lag behind adult approvals by years. Formulation and trial design adjustments complicate paediatric drug development, all of which are vital to accommodate for physiological differences, organ maturation, and rapid weight gain, which are most significant in the youngest children. To facilitate more rapid anti-infective drug development for paediatric populations, regulatory agencies provide guidelines that include extrapolating efficacy and safety data from relevant populations; using pharmacokinetic (PK) bridging and modelling to reduce sample sizes and limit the number of PK studies needed before efficacy analyses; and enrolling age- or weight-based cohorts in parallel rather than sequentially for clinical trials. Ensuring access to approved drugs poses an additional challenge, as uncertainty in demand leads to manufacturing and supply complexity with potentially higher costs that can be a barrier to uptake. Here we summarise challenges in drug development for children living with HIV, which are not unique to antiretrovirals. We aim to propose strategies for how model-based approaches and global partnerships can overcome some of these barriers to accelerate paediatric drug development, with particular reference to HIV, and how lessons learnt from HIV could be extended to other anti-infectives.

Age-Specific ADME Gene Expression in Infant Intestinal Enteroids.

In childhood, developmental changes and environmental interactions highly affect orally dosed drug disposition across the age range. To optimize dosing regimens and ensure safe use of drugs in pediatric patients, understanding this age-dependent biology is necessary. In this proof-of-concept study, we aimed to culture age-specific enteroids from infant tissue which represent its original donor material, specifically for drug transport and metabolism. Enteroid lines from fresh infant tissues (n = 8, age range: 0.3-45 postnatal weeks) and adult tissues (n = 3) were established and expanded to 3D self-organizing enteroids. The gene expression of drug transporters P-gp (ABCB1), BCRP (ABCG2), MRP2 (ABCC2), and PEPT1 (SLC15A1) and drug metabolizing enzymes CYP3A4, CYP2C18, and UGT1A1 was determined with RT-qPCR in fresh tissue and its derivative differentiated enteroids. Expression levels of P-gp, BCRP, MRP2, and CYP3A4 were similar between tissues and enteroids. PEPT1 and CYP2C18 expression was lower in enteroids compared to that in the tissue. The expression of UGT1A1 in the tissue was lower than that in enteroids. The gene expression did not change with the enteroid passage number for all genes studied. Similar maturational patterns in tissues and enteroids were visually observed for P-gp, PEPT1, MRP2, CYP3A4, CYP2C18, and VIL1. In this explorative study, interpatient variability was high, likely due to the diverse patient characteristics of the sampled population (e.g., disease, age, and treatment). To summarize, maturational patterns of clinically relevant ADME genes in tissue were maintained in enteroids. These findings are an important step toward the potential use of pediatric enteroids in pediatric drug development, which in the future may lead to improved pediatric safety predictions during drug development. We reason that such an approach can contribute to a potential age-specific platform to study and predict drug exposure and intestinal safety in pediatrics.

Advancing pediatric drug development in South Asia: Current landscape and vision for the future.

The manuscript summarizes the outcomes of a one-day conference by the South Asian College of American College of Clinical Pharmacology (SAC-ACCP) in July 2023, at Bhopal. The theme of the conference was "Advancing pediatric drug development in South Asia." SAC-ACCP organized this event in Bhopal to foster the discipline of clinical pharmacology and to motivate researchers and physicians in the in the central part of India. The conference featured presentations on regional approaches to pediatric drug development in Asia by pediatric scientific experts from the pharmaceutical industry, regulatory agencies, as well as independent consultancies. The speakers highlighted several important aspects of the evolving regulatory landscape in India and proposed numerous actionable steps in acceleration of pediatric drug development. This commentary provides insights from presentations and the panel discussion at this conference and also makes an attempt to connect to similar discussions that occurred at the SAC-ACCP drug development conference in 2017.

Discussion of the classification of pediatric drug clinical trials in children's hospitals in China.

This study aimed to gain insights into pediatric clinical trials conducted in children's hospitals in China and provide valuable references for the development of children's hospitals and the research and development of pediatric drugs. A comprehensive search was performed on the Chinese Clinical Trial Registry (Chi CTR) and ChinaDrugTrials.org.cn to collect information on all clinical trials involving subjects under 18 years, including those conducted in children's hospitals. The retrieval period was extended until 31 December 2022. A total of 459 pediatric clinical trials were collected, comprising 299 from Chi CTR and 160 from the Drug Clinical Trial Registration and Information Publicity Platform (Information Platform). Post-marketing drug studies and phase III clinical trials accounted for the majority of research stages. These trials covered a wide range of diseases/systems, with a particular focus on respiratory system disorders, tumors, endocrine disorders, and nutritional or metabolic diseases. Chemical drugs constituted the most extensively studied category, while traditional Chinese medicine/natural drugs received comparatively less attention. Clinical trial activities were primarily geographically focused on the eastern coastal regions of China, with multicenter trials being the most predominant. Ethics committee approval was obtained for 427 studies. The pediatric clinical trials conducted by children's hospitals in China have shown an overall upward trend; however, there is limited research focusing on traditional Chinese medicine, along with significant regional and institutional imbalances. Furthermore, there is still room for improvement regarding ethical review processes. It is recommended that children's hospitals enhance their scientific research capabilities while optimizing resource allocation to meet medical service demands effectively. Additionally, fostering more research-focused children's hospitals will contribute to the high-quality development of children's health in China.

Did pediatric drug development advance epilepsy treatment in young patients? It is time for new research goals.

Modern drugs have changed epilepsy, which affects people of all ages. However, for young people with epilepsy, the framework of drug development has stalled. In the wake of the thalidomide catastrophe, the misconception emerged that for people < 18 years of age drugs, including antiseizure medications (ASMs), need separate proof of efficacy and safety, overall called "pediatric drug development". For ASMs, this has changed to some degree. Authorities now accept that ASMs are effective in < 18 years as well, but they still require "extrapolation of efficacy," as if minors were another species. As a result, some of the pediatric clinical epilepsy research over the past decades was unnecessary. Even more importantly, this has hampered research on meaningful research goals. We do not need to confirm that ASMs work before as they do after the 18th birthday. Instead, we need to learn how to prevent brain damage in young patients by preventing seizures and optimize ASMs' uses. Herein we discuss how to proceed in this endeavor.

Pediatric Pharmacology for the Primary Care Provider: Advances and Limitations.

Despite >1 in 5 children taking prescription drugs in the United States, off-label drug use is common. To increase the study of drugs in children, regulatory bodies have enacted legislation to incentivize and require pediatric drug studies. As a result of this legislation, novel trial approaches, and an increase in personnel with pediatric expertise, there have been numerous advancements in pediatric drug development. With this review, we aim to highlight developments in pediatric pharmacology over the past 6 years for the most common disease processes that may be treated pharmacologically by the pediatric primary care provider. Using information extracted from label changes between 2018 and 2023, the published literature, and Clinicaltrials.gov, we discuss advances across multiple therapeutic areas relevant to the pediatric primary care provider, including asthma, obesity and related disorders, mental health disorders, infections, and dermatologic conditions. We highlight instances in which new drugs have been developed on the basis of a deeper mechanistic understanding of illness and instances in which labels have been expanded in older drugs on the basis of newly available data. We then consider additional factors that affect pediatric drug use, including cost and nonpharmacologic therapies. Although there is work to be done, efforts focused on pediatric-specific drug development will increase the availability of evidence-based, labeled guidance for commonly prescribed drugs and improve outcomes through the safe and effective use of drugs in children.

Paediatric Drug Development in China: Current Status and Future Prospects.

For more than two decades, regulatory agencies throughout the world released guidelines, rules and laws to stimulate and assist in paediatric drug development. In 2014, the National Health and Family Planning Commission (now known as the National Health Commission, NHC) and five other departments in China jointly issued 'Several Opinions on Safeguarding Medication for Children', after which several policies and regulations were issued to implement the priority review and approval of paediatric medicinal products and support the development of new drugs, including new dosage forms and strengths, for children. A total of 172 special medicinal products for children were approved from 2018 to 2022. Since 2016, the NHC, together with relevant administrative departments, has formulated and issued four paediatric drug lists containing 129 medicinal products to encourage research and development. At present, approximately 25 of these drugs (at exactly the same dosage forms and strengths as on the lists) have been approved for marketing, including antitumour drugs and immunomodulators, nervous system drugs, drugs for mental disorders and drugs for rare diseases. In this review, we analysed the regulations issued for promoting paediatric drug development in China, including the priority review and approval system, technical guidelines, data protection and financial support policies and general profiles of paediatric drug approval, clinical trials and the addition of information for children in the labels of marketed medicinal products. Finally, we discussed the challenges and possible strategies in the research and development of paediatric drugs in China.

Institutional review of pediatric oncology patients participating in early phase clinical trials.

10042 Background: Phase 1 or phase 1/2 trials are a first step in pediatric cancer drug development with a primary objective of evaluating safety and dosing of new therapies or new combinations. They most commonly enroll patients with relapsed/refractory or very rare cancers and currently there is a paucity of information regarding outcomes for pediatric patients enrolled on phase 1/2 trials. Thus, we sought to describe clinical outcomes of pediatric patients enrolled in phase 1 clinical trials over a 9-year period at a single institution. Methods: We queried our clinical trials management system to generate a list of all pediatric patients who were enrolled and treated on phase 1 or phase 1/2 trials from 2011-2019. We reviewed the electronic medical record to collect baseline demographic and clinical data. We also collected key efficacy and safety endpoints post-enrollment including: time to death (if applicable); objective response to trial therapy; duration on therapy; need for dose modification; and occurrence of DLT. Overall survival was calculated using Kaplan-Meier methods. Results: A total of 224 unique patients accounted for 258 enrollments and 253 episodes of treatment on trial. The median age at trial enrollment was 11 years (range 0-27 years) and 56.2% were male. The majority of patients were white (85.7%) and non-Hispanic (88.2%). English was the primary language for 86.3% of patients and 65.8% of patients had private insurance. Solid tumors were the most common malignancy at 41.0%, followed by brain tumors (34.1%), and hematologic malignancies (24.9%). The majority of patients (60%) had metastatic disease at time of first enrollment. Among episodes of treatment, 51.4% received targeted monotherapy. Median overall survival from first enrollment for 210 patients treated with available vital status was 12.8 months. Among episodes of treatment, 25.2% of patients had an objective response to trial therapy. Stratified by disease type, objective response was documented for 52.9% of patients with hematologic malignancies, 20.5% of patients with CNS tumors, and 15.8% of patients with solid tumors. Patients on trials with cytotoxic-only treatment had the highest objective response (47.5%), while patients treated with cytotoxic plus targeted therapies combinations had the lowest rate (18.9%). The median duration of therapy was 1.5 months. Twenty-seven patients (11.0%) required dose modification and 22 patients (9.0%) had DLT. Conclusions: We present clinical outcomes for a recent cohort of pediatric patients treated on early phase clinical trials. We identified differential response rates to phase 1 therapy by disease and trial-type in a single-center cohort treated over the past decade. These data are immediately informative to discussions between providers and patients/parents regarding expected phase 1 trial outcomes.

Applying Neural ODEs to Derive a Mechanism-Based Model for Characterizing Maturation-Related Serum Creatinine Dynamics in Preterm Newborns.

Serum creatinine in neonates follows complex dynamics due to maturation processes, most pronounced in the first few weeks of life. The development of a mechanism-based model describing complex dynamics requires high expertise in pharmacometric (PMX) modeling and substantial model development time. A recently published machine learning (ML) approach of low-dimensional neural ordinary differential equations (NODEs) is capable of modeling such data from newborns automatically. However, this efficient data-driven approach in itself does not result in a clinically interpretable model. In this work, an approach to deriving an interpretable model with reasonable PMX-type functions is presented. This "translation" was applied to derive a PMX model for serum creatinine in neonates considering maturation processes and covariates. The developed model was compared to a previously published mechanism-based PMX model whereas both models had similar mechanistic structures. The developed model was then utilized to simulate serum creatinine concentrations in the first few weeks of life considering different covariate values for gestational age and birth weight. The reference serum creatinine values derived from these simulations are consistent with observed serum creatinine values and previously published reference values. Thus, the presented NODE-based ML approach to model complex serum creatinine dynamics in newborns and derive interpretable, mathematical-statistical components similar to those in a conventional PMX model demonstrates a novel, viable approach to facilitate the modeling of complex dynamics in clinical settings and pediatric drug development.

Conducting Drug Treatment Trials in Children: Opportunities and Challenges.

Children were often referred to as "therapeutic orphans" in the past due to different reasons such as ethical, regulatory, economic, scientific, etc., ones. They were exposed to avoidable risks while missing out on therapeutic advances. Pediatric patients have suffered from a lack of scientific and regulatory standards (e.g., proper drug testing, authorization of medicines for their use, etc.), although the pharmaceutical legislative framework, which ensures the high standards of safety, quality, and efficacy of medicinal products for use in adults, was developed primarily in response to past "drug disasters," mainly involving children. The adoption of pediatric regulatory initiatives first in the USA and then in Europe and other countries and regions has significantly changed the worldwide frameworks and permanently changed pediatric drug research and development. This article tries to give various perspectives with historical context, a review of the different challenges and opportunities as well as important stakeholders in pediatric drug development. The pediatric trial networks are probably the most important stakeholder that enables efficient patient recruitment, access to better resource utilization, and global collaboration of different stakeholders necessary for performing quality and well-designed clinical trials.

Modern pediatric drug development: Practical case examples and regulatory outcomes from novel applications of modelling

Modern pediatric drug development: Practical case examples and regulatory outcomes from novel applications of modelling