Pediatric Drug Development Research Articles

Development of a Virtual Chinese Pediatric Population Physiological Model Targeting Specific Metabolism and Kidney Elimination Pathways.

Background: Physiologically based pharmacokinetic (PBPK) modeling and simulating may be a powerful tool in predicting drug behaviors in specific populations. It is a mathematical model that relates the pharmacokinetic (PK) profile of a compound with human anatomical characteristics, physiological characteristics, and biochemical parameters. Predictions using PBPK models offer a promising way to guide drug development and can be used to optimize clinical dosing regimens. However, PK data of new drugs in the pediatric population are too limited to guide clinical therapy, which may lead to frequent adverse events or insufficient efficacy for pediatric patients, particularly in neonates and infants. Objective: The objective of this study was to establish a virtual Chinese pediatric population based on the physiological parameters of Chinese children that could be utilized in PBPK models. Methods: A Chinese pediatric PBPK model was developed in Simcyp Simulator by collecting published Chinese pediatric physiological and anthropometric data to use as system parameters. This pediatric population model was then evaluated in the Chinese pediatric population by predicting the pharmacokinetic characteristics of four probe drugs: theophylline (major CYP1A2 substrate), fentanyl (major CYP3A4 substrate), vancomycin, and ceftazidime (renal-eliminated). Results: The predicted maximum concentration (Cmax), area under the curve of concentration-time (AUC), and clearance (CL) for theophylline (CYP1A2 metabolism pathway) and fentanyl (CYP3A4 metabolism pathway) were within two folds of the observed data. For drugs mainly eliminated by renal clearance (vancomycin and ceftazidime) in the Chinese pediatric population, the ratio of prediction to observation for major PK parameters was within a 2-fold error range. Conclusion: The model is a supplement to the previous Chinese population PBPK model. We anticipate the model to be a better representative of the pediatric Chinese population for drugs PK, offering greater clinical precision for medication given to the pediatric population, ultimately advancing clinical development of pediatric drugs. We can refine this model further by collecting more physiological parameters of Chinese children.

Drug Safety in Translational Paediatric Research: Practical Points to Consider for Paediatric Safety Profiling and Protocol Development: A Scoping Review.

Translational paediatric drug development includes the exchange between basic, clinical and population-based research to improve the health of children. This includes the assessment of treatment related risks and their management. The objectives of this scoping review were to search and summarise the literature for practical guidance on how to establish a paediatric safety specification and its integration into a paediatric protocol. PubMed, Embase, Web of Science, and websites of regulatory authorities and learned societies were searched (up to 31 December 2020). Retrieved citations were screened and full texts reviewed where applicable. A total of 3480 publications were retrieved. No article was identified providing practical guidance. An introduction to the practical aspects of paediatric safety profiling and protocol development is provided by combining health authority and learned society guidelines with the specifics of paediatric research. The paediatric safety specification informs paediatric protocol development by, for example, highlighting the need for a pharmacokinetic study prior to a paediatric trial. It also informs safety related protocol sections such as exclusion criteria, safety monitoring and risk management. In conclusion, safety related protocol sections require an understanding of the paediatric safety specification. Safety data from carefully planned paediatric research provide valuable information for children, parents and healthcare providers.

Remdesivir: Preliminary Data and Clinical Use Versus Recommended Use.

* Abbreviations: COVID-19 — : coronavirus disease 2019 FDA — : Food and Drug Administration Remdesivir inhibits viral replication of severe acute respiratory coronavirus 2 in vitro and has been shown to reduce time to recovery in adults with coronavirus disease 2019 (COVID-19). It is currently the only antiviral approved by the Food and Drug Administration (FDA) for the treatment of COVID-19.1–4 Although remdesivir is being used in children with COVID-19, it is not approved for patients <12 years of age. Fortunately, if treatment with remdesivir of COVID-19 meets key assumptions, the drug may qualify for the extrapolation pathway, whereby efficacy data in adults can be used to support efficacy in children. However, safety data cannot be extrapolated; population-specific safety data are needed to support FDA labeling for pediatric use. Thus, we read with anticipation the safety data on compassionate use of remdesivir in 77 children with severe COVID-19 presented by Goldman et al5 in this issue of Pediatrics . Goldman et al5 describe low rates of adverse events, including elevated liver aminotransferase levels and anemia, similar to the safety profile seen in adults receiving remdesivir. In light of these data, we will consider whether the concept of extrapolation could be used to support efficacy of remdesivir in children … Address correspondence to Danny K. Benjamin, MD, PhD, Duke Clinical Research Institute, Durham Centre, Suite 800, 300 W Morgan St., Durham, NC 27701. E-mail: danny.benjamin{at}duke.edu

Pediatric formulation development – Challenges of today and strategies for tomorrow: Summary report from M−CERSI workshop 2019

A workshop on “Pediatric Formulation Development: Challenges of Today and Strategies for Tomorrow” was organized jointly by the University of Maryland’s Center of Excellence in Regulatory Science and Innovation (M−CERSI), the U.S. Food and Drug Administration (FDA) and the International Consortium for Innovation and Quality in Pharmaceutical Development (IQ) Drug Product Pediatric Working Group (PWG). This multi-disciplinary, pediatric focused workshop was held over a two-day period (18–19 Jun 2019) and consisted of participants from industry, regulatory agencies, academia and other organizations from both US and Europe. The workshop consisted of sequential sessions on formulation, analytical, clinical, and regulatory and industry lessons learned and future landscape. Each session began with a series of short framing presentations, followed by facilitated breakout sessions and panel discussion. The formulation session was dedicated to three main topics pertaining to drug product acceptability, excipients in pediatrics and oral administration device considerations. The analytical session discussed key considerations for dosing vehicle selection and analytical strategies for testing of different dosage forms, specifically mini-tablets (multiparticulates). The clinical session highlighted the influence of pediatric pharmacokinetics prediction on formulation design, pediatric drug development strategies and clinical considerations to support pediatric formulation design. The regulatory and industry lessons learned and future landscape session explored the regional differences that exist in regulatory expectations, requirements for pediatric formulation development, and key patient-centric factors to consider when developing novel pediatric formulations. This session also discussed potential collaboration opportunities and tools for pediatric formulation development. This manuscript summarizes the key discussions and outcomes of all the sessions in the workshop with a broadened review and discussion of the topics that were covered.

Harnessing formulation and clinical pharmacology knowledge for efficient pediatric drug development: Overview and discussions from M-CERSI pediatric formulation workshop 2019

A pediatric formulation workshop entitled “Pediatric Formulations: Challenges of Today and Strategies for Tomorrow” was held to advance pediatric drug product development efforts in both pre-competitive and competitive environments. The workshop had four main sessions discussing key considerations of Formulation, Analytical, Clinical and Regulatory. This paper focuses on the clinical session of the workshop. It provides an overview of the discussion on the interconnection of pediatric formulation design and development, clinical development strategy and pediatric clinical pharmacology. The success of pediatric drug product development requires collaboration of multi-disciplinary teams across the pharmaceutical industry, consortiums, foundations, academia and global regulatory agencies. Early strategic planning is essential to ensure alignment among major stakeholders of different functional teams. Such an alignment is particularly critical in the collaboration between formulators and clinical pharmacology teams.

Model-based approach to sampling optimization in studies of antibacterial drugs for infants and young children.

Clinical trials for pediatric indications and new pediatric drugs face challenges, including the limited blood volume due to the patients’ small bodies. In Japan, the Evaluation Committee on Unapproved or Off‐labeled Drugs with High Medical Needs has discussed the necessity of pediatric indications against the background of a lack of Japanese pediatric data. The limited treatment options regarding antibiotics for pediatric patients are associated with the emergence of antibiotic‐resistant bacteria. Regulatory guidelines promote the use of model‐based drug development to reduce practical and ethical constraints for pediatric patients. Sampling optimization is one of the key study designs for pediatric drug development. In this simulation study, we evaluated the precision of the empirical Bayes estimates of pharmacokinetic (PK) parameters based on the sampling times optimized by published pediatric population PK models. We selected three previous PK studies of cefepime and ciprofloxacin in infants and young children as paradigms. The number of sampling times was reduced from original full sampling times to two to four sampling times based on the Fisher information matrix. We observed that the precision of empirical Bayes estimates of the key PK parameters and the predicted efficacy based on the reduced sampling times were generally comparable to those based on the original full sampling times. The model‐based approach to sampling optimization provided a maximization of PK information with a minimum burden on infants and young children for the future development of pediatric drugs.

Study factors associated with the incompletion of clinical trials that include pediatric patients: a retrospective analysis of the European Clinical Trials Database and a lesson from the European region

BackgroundIncomplete clinical trials for pediatric drug development result in a lack of adequate scientific evidence for providing appropriate medication to pediatric populations; this is especially true for Japan. Thus, using the European Clinical Trials Database (EudraCT), this study aimed to identify the factors related to the study design and administration that lead to incompletion of clinical trials that included pediatric patients.MethodsWe focused on clinical trials that included patients under the age of 18 registered in the database, named as the European Clinical Trials Database between January 1, 2014, and December 31, 2018. Two groups of trials were identified: “all cases completed” and “not all cases completed,” reflecting whether they were completed in all participating countries/regions or not. To identify the factors of the occurrence of “not all cases completed,” a logistic regression analysis was performed to calculate the odds ratios and 95% confidence intervals. In total, 142 clinical trials (95 “all cases completed” and 47 “not all cases completed”) were analyzed.ResultsThe logistic regression analysis showed the number of countries in which a clinical trial was conducted to be the only significant factor (odds ratio: 1.3; 95% confidence interval: 1.1-1.5); this was identified as the primary factor for the occurrence of “not all cases completed” in the clinical trials that included pediatric patients.ConclusionOur findings suggest that the feasibility of clinical trials that include pediatric patients, such as whether the countries in which the trial is to be conducted are suitable, must be considered prior to the trial.

Commentary on “Empirical profile Bayesian estimation for extrapolation of historical adult data to pediatric drug development”

Bayesian borrowing has been a long-standing concept, but the difficulty has been that if the current data deviates from the historical information, often referred to as the prior-data conflict, then the simple traditional Bayesian approach will introduce bias and lead to a false positive decision

Opportunities and Challenges in Drug Development for Pediatric Cancers.

The use of targeted small-molecule therapeutics and immunotherapeutics has been limited to date in pediatric oncology. Recently, the number of pediatric approvals has risen, and regulatory initiatives in the United States and Europe have aimed to increase the study of novel anticancer therapies in children. Challenges of drug development in children include the rarity of individual cancer diagnoses and the high prevalence of difficult-to-drug targets, including transcription factors and epigenetic regulators. Ongoing pediatric adaptation of biomarker-driven trial designs and further exploration of agents targeting non-kinase drivers constitute high-priority objectives for future pediatric oncology drug development. SIGNIFICANCE: Increasing attention to drug development for children with cancer by regulators and pharmaceutical companies holds the promise of accelerating the availability of new therapies for children with cancer, potentially improving survival and decreasing the acute and chronic toxicities of therapy. However, unique approaches are necessary to study novel therapies in children that take into account low patient numbers, the pediatric cancer genomic landscape and tumor microenvironment, and the need for pediatric formulations. It is also critical to evaluate the potential for unique toxicities in growing hosts without affecting the pace of discovery for children with these life-threatening diseases.

Hypothalamic-Pituitary-Adrenal Axis Pediatric Safety Studies Submitted to the FDA.

Corticosteroid use has been associated with hypothalamic-pituitary-adrenal (HPA) axis suppression which can predispose the pediatric patient to multiple immune- and growth-related adverse effects. The objectives of this review were to identify the pediatric drug development programs involving corticosteroids and the associated pediatric HPA axis suppression studies submitted to the US Food and Drug Administration (FDA), capture FDA guidance topic related recommendations, and determine the consistency of HPA axis data in prescription corticosteroid labeling. A review of FDA submissions from January 2002 to July 2018 involving corticosteroid products and HPA axis testing in pediatric patients was conducted. The adrenal function testing methods, number of pediatric HPA axis dedicated studies, duration of these studies, and the labeling outcomes were assessed. Of the 437 total drug products that were submitted to FDA, only 36 products were corticosteroids or a corticosteroid combination product yielding a total of 83 pediatric clinical studies. Twenty-four of the 36 products included 37 HPA axis suppression dedicated studies which employed different measurement methods. The pediatric HPA axis suppression trial data collected did not necessitate any new actionable recommendations in the FDA labeling. Future pediatric drug development program goals would be to determine whether HPA axis suppression studies should be conducted, establish optimal testing methods if HPA axis testing is performed, continue to update guidances for industry, and actionable labeling recommendations. However, regulatory policy related to conducting pediatric HPA axis studies requires additional scientific research and discussion by the pediatric drug development community.

Klaus Rose. Considering the Patient in Pediatric Drug Development: How Good Intentions Turned into Harm

Klaus Rose. Considering the Patient in Pediatric Drug Development: How Good Intentions Turned into Harm

Harmonising regulatory approval for antibiotics in children

Antimicrobial resistance represents a substantial threat to the Sustainable Development Goals (SDGs), with a large impact on the health of children worldwide. 1 Alfvén T Dahlstrand J Humphreys D et al. Placing children and adolescents at the centre of the Sustainable Development Goals will deliver for current and future generations. Glob Health Action. 2019; 121670015 Crossref PubMed Scopus (11) Google Scholar , 2 Laxminarayan R Bhutta ZA Antimicrobial resistance—a threat to neonate survival. Lancet Glob Health. 2016; 4: e676-e677 Summary Full Text Full Text PDF PubMed Scopus (29) Google Scholar However, very few paediatric trials for new antibiotics have been done to inform the optimal treatment of multidrug-resistant infections in children. The current drug regulatory framework has evolved from a system that rightly aimed to protect children, yet remains governed by interpretation of laws established in response to historical incidents involving agents that caused harm. 3 National Institute of Medicine (US)Forum on Drug Discovery, Development, and Translation. Addressing the Barriers to Pediatric Drug Development: Workshop Summary. Regulatory Framework, Washington, DC2008 Google Scholar This approach, particularly for medicines from well established classes with a long experience of safe use in children (such as β-lactam penicillins), now unnecessarily complicates the process of paediatric antibiotic development, and is one of the many barriers to children with multidrug-resistant infections being appropriately treated with licensed drugs. Regulatory approval for anti-infectives in childrenWe recognise the challenges in doing clinical trials for anti-infectives in children and thank Phoebe Williams and colleagues1 for highlighting some of these challenges. We have provided clarifications to address some points raised by the authors. Full-Text PDF

Best practices for selection of excipients for paediatrics – Workshop reflection

The development of age appropriate formulations for the paediatric population has become one of the key areas of focus for the pharmaceutical industry – with a subsequent influence on excipient use. Selection of excipients with appropriate safety and tolerability is a major hurdle in paediatric formulation development. Various factors influence selection of excipients, including target age group, route of administration and dosage form. Evaluation of these factors and a clear rationale and justification is expected by the regulators when it comes to selecting excipients for paediatric formulation. Scientists are encouraged to apply the principle of benefit to risk balance to assess the suitability of excipients to the specific paediatric population for whom the formulation is intended. In order to understand how scientists approach the task of establishing the risk to benefit analysis, a workshop was organised by the European Paediatric Formulation Initiative (EuPFI) to reflect on the current scenario and the different practices employed by formulation scientists in the selection of excipients for paediatric formulations. Aspects assessed by regulators were also canvassed. Finally, the participants were asked to comment on how selecting excipients for use in paediatric formulations may differ from the considerations applied in selecting excipients for formulations for other age groups. Based on the workshop discussion, some recommendations and questions to consider emerged regarding the selection of excipients in paediatric drug development. These best practice recommendations provided a good starting point for a more systematic strategy for selecting excipients for paediatric formulation development.

Research on the development of cancer drugs for children

The development of pediatric cancer drugs is inefficient and must requires a significant development to improve the current situation. According to the research on the development of pediatric cancer drugs, the market condition is analyzed and compared with adult cancer drugs. It is found that even though the drug market for pediatric cancer is significantly smaller than adult cancer’s drug market, it is still important that pediatric cancer drugs are developed in order to better serve the treatment for childhood cancer, and increase the survival rate for malign cancer cases. Through thorough research it also appeared that while the government provides some beneficial programs and insurances for children experiencing pediatric cancer, better insurance plans should be identified. Another important finding throughout research results in the government and legislation area, where the pediatric cancer drugs development process is analysed and has found some potential for the future. As a whole, the effort of the government in both the drug development period and the legislation area with the combination of big pharmaceutical companies’ efforts and the potential creation of new kinds of insurances, the situation for pediatric cancer drugs development can experience a positive change.

Development of a Pediatric Mini-Tablet Formulation for Expedited Preclinical Studies.

Multiple considerations are essential to address the main challenges of dose flexibility and patient adherence in pediatric drug development, particularly for oncology. Mini-tablets, 2mm in diameter, were manufactured using a rotary tablet press at a set weight and compression force level. The physical characteristics were consistent for mini-tablets throughout multiple batches. Polymeric amorphous solid dispersion (ASD) was used as a solubility enhancing technique to increase solubility and exposure of lapatinib. The effects of the polymeric excipient and disintegrant on drug release properties were investigated. While having a lower apparent solubility and shorter storage stability, hydroxypropyl methylcellulose E3 (HPMCE3) formulation provided a higher percentage of drug release compared to hydroxypropyl methylcellulose phthalate (HPMCP). The intermolecular interaction within the ASD system plays a role in the level of apparent solubility, physical stability, and concentration of free drug available in an aqueous environment. Juvenile porcine models at two different weight groups (10 and 20kg) were used to obtain the pharmacokinetic parameters of lapatinib. While the dose-normalized exposure of drug was found to be lower in the pig study, the dose flexibility of mini-tablets enabled a constant dose level to be administered to achieve equivalent plasma concentration-time profiles between the two groups. This linear scaling in the amount of drug in pediatric and adult population has also been observed in human clinical studies.

Questionnaire Survey of Pharmacy Students after Long-term Practical On-site Training Reveals Points for Development of Pediatric Drugs

Questionnaire Survey of Pharmacy Students after Long-term Practical On-site Training Reveals Points for Development of Pediatric Drugs

Activity of Japan Paediatric Society Paediatric Drug Development Network (JPedNet)

Activity of Japan Paediatric Society Paediatric Drug Development Network (JPedNet)

Pharmaceutical Industry Perspectives for Pediatric Drug Development

Pharmaceutical Industry Perspectives for Pediatric Drug Development

International Trends of Pediatric Drug Development

International Trends of Pediatric Drug Development

The Neonatal and Juvenile Pig in Pediatric Drug Discovery and Development.

Pharmacotherapy in pediatric patients is challenging in view of the maturation of organ systems and processes that affect pharmacokinetics and pharmacodynamics. Especially for the youngest age groups and for pediatric-only indications, neonatal and juvenile animal models can be useful to assess drug safety and to better understand the mechanisms of diseases or conditions. In this respect, the use of neonatal and juvenile pigs in the field of pediatric drug discovery and development is promising, although still limited at this point. This review summarizes the comparative postnatal development of pigs and humans and discusses the advantages of the juvenile pig in view of developmental pharmacology, pediatric diseases, drug discovery and drug safety testing. Furthermore, limitations and unexplored aspects of this large animal model are covered. At this point in time, the potential of the neonatal and juvenile pig as nonclinical safety models for pediatric drug development is underexplored.