How to select the initial dose for a pediatric study?

In typical clinical development programs, a new drug is first developed for the adult use. Drugs are often approved for adult use or in the process of obtaining approval in adults in the target indication before pediatric development is initiated. In designing the first pediatric clinical trial, one of the challenges is to select the initial dose to be tested. The ICH E11 R1 guidance advises that chronologic age alone may not always be the most appropriate categorical determinant to define developmental subgroups in pediatric studies. In this manuscript, the approaches to utilize available data in adults related to those factors beyond age to inform the starting dose selection in pediatric drug development are discussed. Practical considerations and approaches are provided for informing pediatric starting dose. Additional considerations to use pre-clinical information are provided in the case when adult information is limited or not available.

"Pediatric" Drug Studies Might Be the Largest Abuse in Medical Research in History. It Is Time for Lawyers to Step In.

A new type of research has emerged with United States and European Union pediatric laws that request/demand separate clinical studies for vaccines and drugs in minors less than 18 years of age. Physiologically, minors mature before their 18th birthday. Medicine treats the body, not the administrative status. Many "pediatric" studies are performed in minors that bodily are no longer children, which makes them pointless. Traditional malpractice litigation in clinical research involves patients that were harmed in clinical studies. In the new type of "pediatric" studies, drugs known to work in humans are retested, pretending that "children" are uniquely different, which is incorrect. Minors are not another species. Patients are not treated at all (placebo group) or below standard-of-care (comparison to outdated treatment). Pediatric laws are the law, but not a free pass for harming patients. Where "pediatric" studies violate accepted norms of medical practice, lawyers should be aware of this challenge at the interface of medicine and law.

Pharmacokinetic/pharmacodynamic data extrapolation models for improved pediatric efficacy and toxicity estimation, with application to secondary hyperparathyroidism.

In most drug development settings, the regulatory approval process is accompanied by extensive studies performed to understand the drug's pharmacokinetic (PK) and pharmacodynamic (PD) properties. In this article, we attempt to utilize the rich PK/PD data to inform the borrowing of information from adults during pediatric drug development. In pediatric settings, it is especially crucial that we are parsimonious with the patients recruited for experimentation. We illustrate our approaches in the context of clinical trials of cinacalcet for treating secondary hyperparathyroidism in pediatric and adult patients with chronic kidney disease, where we model both parathyroid hormone (efficacy endpoint) and corrected calcium levels (safety endpoint). We use population PK/PD modeling of the cinacalcet data to quantitatively assess the similarity between adults and children, and use this information in various hierarchical Bayesian adult borrowing rules whose statistical properties can then be evaluated. In particular, we simulate the bias and mean square error performance of our approaches in settings where borrowing is and is not warranted to inform guidelines for the future use of our methods.

Pediatric drug development in China: Reforms and challenges.

In China, child and adolescent pediatricians often face challenges in treating children with the appropriate medications. Within the last 8 years, the Chinese government has already initiated a series of policies to promote development of age-appropriate medicines for children. In this study,we introduced the current status of pediatric drugs, obstacles for pediatric drugs development and regulatory reforms in China. The lack of label information in drugs for children, inadequacy of age-appropriate dosage forms and strengths, and shortage of pediatric drugs are some of the problems commonly faced. There exists neither mandatory requirements nor enough financial drivers for development of pediatric medicines. Though some progress in terms of pediatric drugs development as well as distribution have been made by Chinese government over past years, further efforts are necessary to improve availability of pediatric medications.

Global Harmonization of Pediatric Drug Development: Critical for Progress for Developing Safe and Effective Therapeutic Agents for Children.

The article, "Questionable Industry-Sponsored Studies in Children and Adolescents in Slovenia" provides an opportunity to discuss evolving US and EU legislative measures to improve the available clinical trial-derived pediatric data and provide coherent labeling for pediatric providers in dosing of drugs for children.

Questionable Industry-Sponsored Postneonatal Pediatric Studies in Slovenia.

BACKGROUND: US and EU pediatric laws promote industry-sponsored pediatric studies, based on the therapeutic orphans concept that claims discrimination of children in drug treatment and drug development. OBJECTIVE: We investigated the medical validity of international pediatric studies with centers in Slovenia, an EU member state, and challenge their medical utility. METHODS: We analyzed international industry-sponsored pediatric studies with centers in Slovenia, listed in www.ClinicalTrials.gov, for their medical value. RESULTS: Most pediatric studies triggered by the US Food and Drug Administration and by the European Medicines Agency were/are without medical or scientific value. They were/are formally and regulatorily justified, but lack medical sense and thus were/are unethical. Several even harm children and/or adolescents with serious diseases by exposing them to placebo or substandard treatment. CONCLUSIONS: Pediatric studies triggered by US and EU regulatory demands are a serious abuse of nonneonatal children and adolescents in Slovenia and worldwide. They are medically redundant at best and often deter patients from effective innovative personalized therapy. They also exclude young patients from reasonable studies. Institutional review boards/ethics committees should be alerted, should critically review all ongoing pediatric studies, should suspend those found to be questionable, and should reject newly submitted questionable ones.

The Challenges of Pediatric Drug Development.

INTRODUCTION AND BACKGROUND: "Pediatric Drug Development" is being used to describe not the development of drugs for children, but rather the planning & conducting separate efficacy and safety (E&S) studies requested/demanded by regulatory authorities designed to produce pediatric labels. Pediatric studies required for drug approval enroll "children"; defined as <17 years of age (US Food and Drug Administration [FDA])/ <18 years (European Union [EU]). The medical rationale for study designs was examined. MATERIAL & METHODS: International industry-sponsored pediatric E&S studies registered in www.clinicaltrials.gov were analysed along with the history of US/EU laws, published literature, internet-retrieved regulatory documents, and regulatory/ American Academy of Pediatrics (AAP) justifications for doing separate pediatric E&S studies. RESULTS: US/EU regulators utilize an official, but non-physiological definition of childhood based on an age limit of 17/18 years. This definition, which blurs the interface between medicine and law, emerged after clinical studies became required for drug approval in 1962 prompting drug manufacturers to insert pediatric warnings into product information. Intended largely as legal protection against liability, they were interpreted medically. Absorption, distribution, metabolism, excretion mature rapidly. Drug toxicities seen in newborns during the first months of life were cited by AAP/FDA in warnings of dangers of drugs in all "children" including in adolescents who are physiologically no longer children. Warnings were/are exaggerated, exploit/ed parents' protective instincts and fears, and increase/d pediatric clinical trial activity. Conflicts of interest created by this increased activity involve research funding, career status & advancement, commercial profits. DISCUSSION: FDA/EMA-requested/demanded "pediatric" studies were identified which lack medical sense at best, others actually harm young patients by impeding use of superior, effective treatments. Separate labels for different indications make medical sense; separate approval in persons above/below 17/18 years of age does not. CONCLUSIONS: Pediatric medical research should be restricted to studies which meet important medical needs of all recruited young patients, which generate information that cannot be obtained by other study designs, and do not limit access to superior alternative therapies. Clinical centers, investigators, and IRBs/ECs should more carefully examine studies for unjustified regulatory demands, prevention of subjects' access to superior treatments, and undeclared COI's. Questionable studies should not be approved and ongoing ones should be suspended.

Global Pediatric Drug Development.

BACKGROUND: The EU Paediatric Regulation was introduced in 2007. In the United States, specific paediatric legislation has existed for even longer. This overview describes the similarities and differences in the legislation and provides input on how to achieve a global, harmonized pediatric development plan. OBJECTIVES: The overview aims to investigate, through discussions and case examples, how to achieve pediatric medicines development fulfilling the expectations of the authorities as well as sponsors. METHODS: The pediatric legislation used in the European Union and United States are compared, and case studies for pediatric development plans where a global harmonized plan was eventually achieved are discussed. RESULTS: The case studies demonstrate some difficulties in getting to the goal of globally aligned pediatric plan development; however, recent initiatives from EMA and FDA are to a large degree addressing such challenges. CONCLUSIONS: Global pediatric drug development is a evolving field, and with recent initiatives from the European Medicines Agency and US Food and Drug Administration, this goal is definitively attainable. (Curr Ther Res Clin Exp. 2019; 80:XXX-XXX).

Pediatric drug information available at the time of new drug approvals: A cross-sectional analysis.

PURPOSE: Greater than 50% of drugs lack pediatric labeling information, resulting in widespread "off-label" use in children. To increase pediatric prescribing information, the Pediatric Research Equity Act (PREA) was passed in 2003, requiring new drug applications to include pediatric assessments. We evaluated the study of new drugs in children since PREA was implemented. METHODS: We performed a cross-sectional analysis of new drug applications submitted to the FDA from December 2003 to July 2012, using publicly available documents at Drugs@FDA. We calculated the proportion of new drugs that included a pediatric assessment at the time of approval and at a final review performed in July 2016. RESULTS: We identified 92 new drugs requiring pediatric assessments. Only 20 (21.7%) had been fully studied in children at the time of approval, while 9 (9.8%) had been partially assessed, and 63 (68.5%) did not have pediatric data. Among drugs approved without pediatric assessments, 4.2% met FDA deferral deadlines and 34.9% eventually submitted pediatric data. At the time of our final review, allowing for a mean of 8.6 years since drug approval, 57.6% of new drugs had not been fully assessed in children. The mean time between approval in adults and availability of pediatric data for drugs approved without pediatric assessments was 6.5 years. CONCLUSIONS: These results represent a comprehensive evaluation of the study of new drugs in children and demonstrate that many drugs continue to be approved without pediatric data. Our findings serve to inform approaches to strengthen adherence to PREA requirements.

Model Informed Pediatric Development Applied to Bilastine: Ontogenic PK Model Development, Dose Selection for First Time in Children and PK Study Design.

PURPOSE: Bilastine is an H1 antagonist whose pharmacokinetics (PK) and pharmacodynamics (PD) have been resolved in adults with a therapeutic oral dose of 20 mg/day. Bilastine has favorable characteristics for use in pediatrics but the PK/PD and the optimal dose in children had yet to be clinically explored. The purpose is to: (1) Develop an ontogenic predictive model of bilastine PK linked to the PD in adults by integrating current knowledge; (2) Use the model to design a PK study in children; (3) Confirm the selected dose and the study design through the evaluation of model predictability in the first recruited children; (4) Consider for inclusion the group of younger children (< 6 years). METHODS: A semi-mechanistic approach was applied to predict bilastine PK in children assuming the same PD as described in adults. The model was used to simulate the time evolution of plasma levels and wheal and flare effects after several doses and design an adaptive PK trial in children that was then confirmed using data from the first recruits by comparing observations with model predictions. RESULTS: PK/PD simulations supported the selection of 10 mg/day in 2 to <12 year olds. Results from the first interim analysis confirmed the model predictions and design hence trial continuation. CONCLUSION: The model successfully predicted bilastine PK in pediatrics and optimally assisted the selection of the dose and sampling scheme for the trial in children. The selected dose was considered suitable for younger children and the forthcoming safety study in children aged 2 to <12 years.

A hierarchical Bayesian approach for combining pharmacokinetic/pharmacodynamic modeling and Phase IIa trial design in orphan drugs: Treating adrenoleukodystrophy with Lorenzo's oil.

X-linked adrenoleukodystrophy (X-ALD) is a rare, progressive, and typically fatal neurodegenerative disease. Lorenzo's oil (LO) is one of the few X-ALD treatments available, but little has been done to establish its clinical efficacy or indications for its use. In this article, we analyze data on 116 male asymptomatic pediatric patients who were administered LO. We offer a hierarchical Bayesian statistical approach to understand LO pharmacokinetics (PK) and pharmacodynamics (PD) resulting from an accumulation of very long-chain fatty acids. We experiment with individual- and observational-level errors and various choices of prior distributions and deal with the limitation of having just one observation per administration of the drug, as opposed to the more usual multiple observations per administration. We link LO dose to the plasma erucic acid concentrations by PK modeling, and then link this concentration to a biomarker (C26, a very long-chain fatty acid) by PD modeling. Next, we design a Bayesian Phase IIa study to estimate precisely what improvements in the biomarker can arise from various LO doses while simultaneously modeling a binary toxicity endpoint. Our Bayesian adaptive algorithm emerges as reasonably robust and efficient while still retaining good classical (frequentist) operating characteristics. Future work looks toward using the results of this trial to design a Phase III study linking LO dose to actual improvements in health status, as measured by the appearance of brain lesions observed via magnetic resonance imaging.

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.

Precision cancer medicine platform trials: Concepts and design of AcSé-ESMART.

Precision cancer medicine brought the promise of improving outcomes for patients with cancer. High-throughput molecular profiling of tumors at treatment failure aims to direct a patient to a treatment matched to the tumor profile. In this way, improved outcome has been achieved in a small number of patients whose tumors exhibit unique targetable oncogenic drivers. Most cancers, however, contain multiple genetic alterations belonging to and of various hallmarks of cancer; for most of these alterations, there is limited knowledge on the level of evidence, their hierarchical roles in oncogenicity, and utility as biomarkers for response to targeted treatment(s). We developed a proof-of-concept trial that explores new treatment strategies in a molecularly-enriched tumor-agnostic, pediatric population. The evaluation of novel agents, including first-in-child molecules, alone or in combination, is guided by the available understanding of or hypotheses for the mechanisms of action of the diverse cancer events. Main objectives are: to determine 1) recommended phase 2 doses, 2) activity signals to provide the basis for disease specific development, and 3) to define new predictive biomarkers. Here we outline concepts, rationales and designs applied in the European AcSé-ESMART trial and highlight the feasibility but also complexity and challenges of such innovative platform trials.

Pharmacogenomics and pediatric drug development: science and political power. A narrative review.

INTRODUCTION: Pharmacogenomics (PGx) investigates how genomes control enzyme expression. Developmental pharmacology (DP) describes the temporal sequence of enzymes impacting absorption, distribution, metabolism, and excretion (ADME) of food and drugs. AREAS COVERED: US and European Union (EU) legislation facilitate and/or enforce pediatric studies for all new drugs, called overall 'pediatric drug development' (PDD). DP and PDD look at patients' chronological age, but oscillate between legal and physiological meanings of the term 'child.' Children's bodies become mature with puberty. EXPERT OPINION: Decades after first DP observations in babies, PGx offers a better understanding of the variability of safety and efficacy of drugs, of the process of aging, and of shifting enzyme patterns across aging. We should rethink and revise outdated interpretations of ADME changes in minors. The Declaration of Helsinki forbids pointless studies that some pediatric researchers and regulatory agencies, more so the EMA than the FDA, demand pointless pediatric studies is regrettable. Medicine needs to differentiate between legal and physiological meanings of the term 'child' and should use objective measures of maturity.

Implications of Pediatric Initiatives on CNS Drug Development for All Ages-2020 and Beyond: Second of Three Sets of Expanded Proceedings from the 2020 ISCTM Autumn Conference on Pediatric Drug Development.

This article expands upon a session, titled "Implications of Pediatric Initiatives on CNS Drug Development for All Ages-2020 and Beyond," that was presented as part of a two-day meeting on pediatric drug development at the International Society for Central Nervous System (CNS) Clinical Trials and Methodology (ISCTM) Autumn Conference in Boston, Massachusetts, in October 2020. Speakers from various areas of pediatric drug development addressed a variety of implications of including children in drug development programs. The speakers wrote summaries of their talks, which are included here. The session's lead chair was Dr. Gahan Pandina, who wrote introductory and closing comments. Dr. Joseph Horrigan addressed the current landscape of pediatric development programs. Dr. Gahan Pandina addressed how the approach to research in pediatric populations affects the drug development process and vice versa. Dr. Alison Bateman-House discussed the ethical implications of research in the pediatric population. Dr. Luca Pani discussed some of the global regulatory issues and challenges concerning research in pediatric patients. Dr. Judith Kando served as a discussant and posed new questions about means of facilitating pediatric research. Finally, Dr. Gahan Pandina provided closing comments and tied together the presented issues. This paper should serve as an expert-informed reference to those interested and involved in CNS drug development programs that are aimed at children and/or required, through regulations, to include children as part of the approval process.

Development of a neonatal Göttingen Minipig model for dose precision in perinatal asphyxia: technical opportunities, challenges, and potential further steps.

Animal models provide useful information on mechanisms in human disease conditions, but also on exploring (patho)physiological factors affecting pharmacokinetics, safety, and efficacy of drugs in development. Also, in pediatric patients, nonclinical data can be critical for better understanding the disease conditions and developing new drug therapies in this age category. For perinatal asphyxia (PA), a condition defined by oxygen deprivation in the perinatal period and possibly resulting in hypoxic ischemic encephalopathy (HIE) or even death, therapeutic hypothermia (TH) together with symptomatic drug therapy, is the standard approach to reduce death and permanent brain damage in these patients. The impact of the systemic hypoxia during PA and/or TH on drug disposition is largely unknown and an animal model can provide useful information on these covariates that cannot be assessed separately in patients. The conventional pig is proven to be a good translational model for PA, but pharmaceutical companies do not use it to develop new drug therapies. As the Göttingen Minipig is the commonly used pig strain in nonclinical drug development, the aim of this project was to develop this animal model for dose precision in PA. This experiment consisted of the instrumentation of 24 healthy male Göttingen Minipigs, within 24 h of partus, weighing approximately 600 g, to allow the mechanical ventilation and the multiple vascular catheters inserted for maintenance infusion, drug administration and blood sampling. After premedication and induction of anesthesia, an experimental protocol of hypoxia was performed, by decreasing the inspiratory oxygen fraction (FiO2) at 15%, using nitrogen gas. Blood gas analysis was used as an essential tool to evaluate oxygenation and to determine the duration of the systemic hypoxic insult to approximately 1 h. The human clinical situation was mimicked for the first 24 h after birth in case of PA, by administering four compounds (midazolam, phenobarbital, topiramate and fentanyl), frequently used in a neonatal intensive care unit (NICU). This project aimed to develop the first neonatal Göttingen Minipig model for dose precision in PA, allowing to separately study the effect of systemic hypoxia versus TH on drug disposition. Furthermore, this study showed that several techniques that were thought to be challenging or even impossible in these very small animals, such as endotracheal intubation and catheterization of several veins, are feasible by trained personnel. This is relevant information for laboratories using the neonatal Göttingen Minipig for other disease conditions or drug safety testing.

Model-Informed Approach Supporting Approval of Nexviazyme (Avalglucosidase Alfa-ngpt) in Pediatric Patients with Late-Onset Pompe Disease.

In August 2021, the US Food and Drug Administration approved Nexviazyme (avalglucosidase alfa-ngpt) for intravenous infusion to treat patients 1 year of age and older with late-onset Pompe disease (LOPD). The effectiveness and safety were studied in patients with LOPD and patients with infantile-onset Pompe disease (IOPD). The dosage(s) tested in clinical trials was 20 mg/kg every other week (qow) in patients with LOPD and 20 mg/kg and 40 mg/kg qow in patients with IOPD. While patients 3 years old and greater with LOPD were eligible for participation in the pivotal trial, the youngest patient enrolled was 16 years old. Therefore, pediatric patients with LOPD were not well represented in the clinical trial. The prevalence of LOPD in pediatrics is extremely low. Thus, conducting a clinical trial in pediatric patients with LOPD would be challenging. Given the similar pathophysiology, mechanism of action, and disease manifestations across the age spectrum of patients with LOPD, the approved dosages for pediatric patients younger than 16 years old with LOPD were based on extrapolation of efficacy using a model-informed exposure bridging strategy, leveraging the safety data from pediatric patients with IOPD. Specifically, the exposure associated with 20 mg/kg qow in adult patients with LOPD was the target exposure for bridging of efficacy. The safety data obtained with 40 mg/kg qow in patients with IOPD was leveraged to support approval in pediatric patients with LOPD aged 1 year and older. This article illustrates a regulatory use of model-informed extrapolation approach for dose selection in pediatric patients with a rare disease.

Patient Centricity: Design and Conduct of Clinical Trials in Orphan Diseases: Third of Three Sets of Expanded Proceedings from the 2020 ISCTM Autumn Conference on Pediatric Drug Development.

This article expands on a session, titled "Patient Centricity: Design and Conduct of Clinical Trials in Orphan Diseases," that was presented as part of a two-day meeting on Pediatric Drug Development at the International Society for Central Nervous System (CNS) Clinical Trials and Methodology (ISCTM) Autumn Conference in Boston, Massachusetts, in October 2020. Speakers from various areas of pediatric drug development addressed a variety of implications of including children in drug development programs, including implications for rare/orphan diseases. The speakers have written summaries of their talks. The session's lead Chair was Dr. Joan Busner, who wrote introductory and closing comments. Dr. Simon Day, regulatory consultant, outlined some of the past mistakes that have plagued trials that did not consult with patient groups in the early design phase. Dr. Atul Mahableshwarkar provided an industry perspective of a recent trial that benefited from the inclusion of patient input. Drs. Lucas Kempf and Maria Sheean provided regulatory input from the perspectives of the United States (US) Food and Drug Administration (FDA) and European Medicines Agency (EMA), respectively. Dr. Judith Dunn outlined a novel approach for assessing and rank ordering patient and clinician clinical meaningfulness and the disconnect that may occur. Dr. Busner provided closing comments, tied together the presented issues, and provided a synopsis of the lively discussion that followed the session. In addition to the speakers above, the discussion included two representatives from patient advocacy groups, as well as an additional speaker who described the challenges of conducting a pediatric trial in the US and European Union (EU), given the often competing regulatory requirements. This article should serve as an expert-informed reference to those interested and involved in CNS drug development programs that are aimed at children and rare diseases and seek to ensure a patient-centric approach.