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Children
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Development of Medicines for Paediatric and Rare Diseases
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Development of Medicines for Paediatric and Rare Diseases

A topical collection in Children (ISSN 2227-9067).

Viewed by 69584

Editors

Prof. Dr. Jane Grant-Kels

E-Mail Website
Collection Editor
Department of Dermatology, University of Connecticut Health Center, Farmington, CT 06030, USA
Interests: melanoma; skin cancer; atypical nevi; reflectance confocal microscopy
Dr. Klaus Rose

E-Mail Website
Collection Editor
Klausrose Consulting, Aeussere Baselstrasse 308, 4125 Riehen, BS, Switzerland
Interests: paediatric drug development; regulatory, societal and scientific aspects of drug development; interface of regulatory, scientific, historical and political aspects in drug development and paediatric drug development; medicines for children; drug development for rare, paediatric, and rare paediatric diseases
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Johannes N. Van den Anker

E-Mail Website
Collection Editor
1. Department of Paediatric Pharmacology and Pharmacometrics, University Children's Hospital Basel, University of Basel, CH-4031 Basel, Switzerland
2. Division of Clinical Pharmacology, Children's National Hospital, Washington, DC 20310, USA
3. Intensive Care and Department of Pediatric Surgery, Erasmus MC Sophia Children's Hospital, 3015 CN Rotterdam, The Netherlands
Interests: developmental pharmacology; neonatal pharmacology; paediatric pharmacology; neonatal medicine; neonatal infectious diseases; pharmacokinetics; pharmacodynamics; neonatal clinical trials
Special Issues, Collections and Topics in MDPI journals

Topical Collection Information

Dear Colleagues,

The value of licensed and appropriately labeled medicines for children and adults is increasingly a focus of public awareness. This is, for a large part, the result of US and EU legislation on paediatric and orphan diseases. However, paediatric clinical practice has changed less than expected, and the initial enthusiasm has been replaced by a more realistic assessment. Breakthrough therapeutic innovations have been introduced in the last decades, e.g. for cystic fibrosis, metabolic diseases or hormonal defects. However, none of these were triggered by paediatric legislation. The aim of this conference and its related collection is to provide an update on both state-of-the-art methodology and operational challenges in research & development of paediatric and rare diseases. It aims at re-evaluating what is needed for more progress in the development of treatments for both paediatric and rare diseases. We welcome original research, review, opinion papers, editorials, or short communications on the following topics: paediatric legislation, commercial drug development, development of orphan and paediatric drugs, paediatric clinical research, developmental pharmacology, neonatal pharmacology, paediatric pharmacology, neonatal medicine, neonatal infectious diseases, pharmacokinetics, pharmacodynamics, and neonatal clinical trials.


Dr. Klaus Rose
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the collection website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Children is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2400 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Better Medicines for Children
  • Paediatric Drug Development
  • Paediatric Formulations
  • Juvenile Animal Studies in Drug Development
  • Age-Specific Formulations
  • Paediatric Clinical Pharmacology
  • Neonatal Clinical Pharmacology
  • Developmental Pharmacology
  • Pharmacokinetics
  • Pharmacodynamics
  • Neonatal Clinical Trials
  • Inclusion of paediatric aspects in drug development
  • Children and history of pharmacy
  • Children and history of medicine
  • Children and society

Published Papers (12 papers)

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2023

Jump to: 2020, 2017, 2015

8 pages, 2369 KiB  
Case Report
Pediatric Gaucher Disease Presenting with Massive Splenomegaly and Hepatic Gaucheroma
by Gianluca Bossù, Laura Pedretti, Lorenzo Bertolini and Susanna Esposito
Children 2023, 10(5), 869; https://doi.org/10.3390/children10050869 - 12 May 2023
Cited by 4 | Viewed by 1543
Abstract
Gaucher Disease (GD) is a condition resulting from an autosomal recessive inheritance pattern, characterized by a deficiency of the lysosomal enzyme beta-glucocerebrosidase. This leads to the accumulation of glucocerebroside and other glycolipids in multiple tissues, causing damage to various organ systems. The diagnosis [...] Read more.
Gaucher Disease (GD) is a condition resulting from an autosomal recessive inheritance pattern, characterized by a deficiency of the lysosomal enzyme beta-glucocerebrosidase. This leads to the accumulation of glucocerebroside and other glycolipids in multiple tissues, causing damage to various organ systems. The diagnosis of GD can be challenging due to its heterogeneity, non-specific symptoms, and variability across different geographic regions and age groups. Although GD is suspected based on symptoms or signs, the diagnosis is confirmed through the measurement of deficient b-glucocerebrosidase activity and the identification of biallelic pathogenic variants in the GBA gene. Intravenous enzyme replacement therapy (ERT) is recommended for GD patients. In this paper, we report a case of a 2-year and 8-month-old girl with massive splenomegaly and radiological finding of hepatic gaucheroma, in whom a genetic study showed homozygous mutation on the GBA gene at c.1448T>C (p.Leu483Pro) and certified the diagnosis of GD. This patient represents the youngest child reported to have gaucheroma and also the first one presenting with gaucheroma at the diagnosis and not during the follow up, highlighting that GD should be routinely included in the differential diagnosis of children presenting with splenomegaly and hepatomegaly, taking into account that the early start of ERT can change the natural history of the disease-preventing serious complications. Full article
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2020

Jump to: 2023, 2017, 2015

16 pages, 893 KiB  
Article
Is It Possible for Children in Duchenne Muscular Dystrophy to Preserve Cardiac Function with Medical Assistance?
by Han Geul Kim, Lucy Youngmin Eun and Han Ki Park
Children 2020, 7(11), 249; https://doi.org/10.3390/children7110249 - 22 Nov 2020
Cited by 3 | Viewed by 2084
Abstract
In patients with Duchenne muscular dystrophy (DMD), death secondary to cardiac or respiratory failure typically occurs in the second or third decade without treatment. Although cardiac dysfunction is treated with standard heart-failure strategies, it remains insufficient in DMD children. The purpose of this [...] Read more.
In patients with Duchenne muscular dystrophy (DMD), death secondary to cardiac or respiratory failure typically occurs in the second or third decade without treatment. Although cardiac dysfunction is treated with standard heart-failure strategies, it remains insufficient in DMD children. The purpose of this study was to evaluate the efficiency of cardiac medication and noninvasive ventilator support in DMD cardiomyopathy children with analyzing echocardiographic data. Forty-eight DMD children patients were included and divided into 2 groups by left ventricular (LV) ejection fraction (EF) at the time of initial treatment. Group 1: LV EF ≥ 45% and Group 2: LV EF < 45%. p-values were calculated using a Linear mixed model to estimate the association between cardiac medications and echocardiographic measurements. Before and after cardiac medications, the change values were significantly different in interventricular septal thickness at end diastole (IVSd), interventricular septal thickness at end systole (IVSs), left ventricular internal diameter end systole (LVIDs), left ventricular posterior wall thickness end diastole (LVPWd), ejection fraction (EF), fractional shortening (FS), deceleration time (DT), DT slope, Lat A’ and Lat E/E’ (p < 0.05). Group 2 patients revealed to take more kinds of cardiac medications than Group 1 (p < 0.05) including ACEIs, beta-blocker, and inotropics, then LV EF was better preserved in Group 2 than Group 1. It is certainly helpful to take individualized medical combination therapy including inotropic agents for cardiomyopathy in DMD children patients with EF < 45%. Full article
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7 pages, 1986 KiB  
Case Report
Bilateral Pulmonary Embolism in a 12-Year-Old Girl with Steroid-Resistant Nephrotic Syndrome
by Osama Y. Safdar, Rahaf H. Rajab, Rand G. Alghanemi, Gazal A. Tantawi, Noora A. Alsulami, Aeshah A. Alsayed and Abdullah K. Habiballah
Children 2020, 7(6), 62; https://doi.org/10.3390/children7060062 - 15 Jun 2020
Cited by 1 | Viewed by 3328
Abstract
Nephrotic syndrome is the most common glomerular disease among children. Although most cases respond to steroid therapy, approximately 10–20% of patients exhibit resistance to conventional steroid therapy and are labeled as steroid-resistant. Such patients are at risk of complications, including infection, thrombosis, and [...] Read more.
Nephrotic syndrome is the most common glomerular disease among children. Although most cases respond to steroid therapy, approximately 10–20% of patients exhibit resistance to conventional steroid therapy and are labeled as steroid-resistant. Such patients are at risk of complications, including infection, thrombosis, and chronic kidney disease. Nephrotic syndrome is considered a thrombogenic condition. Pulmonary embolism is associated with high mortality, and early treatment is essential for the survival of patients. Here, we report the case of a 12-year-old girl with late steroid resistance who developed bilateral pulmonary embolism. Full article
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2017

Jump to: 2023, 2020, 2015

167 KiB  
Commentary
Key Challenges in the Search for Innovative Drug Treatments for Special Populations. Converging Needs in Neonatology, Pediatrics, and Medical Genetics
by Stuart MacLeod
Children 2017, 4(8), 68; https://doi.org/10.3390/children4080068 - 04 Aug 2017
Cited by 1 | Viewed by 4254
Abstract
The explosion of knowledge concerning the interplay of genetic and environmental factors determining pathophysiology and guiding therapeutic choice has altered the landscape in pediatric clinical pharmacology and pharmacy. The need for innovative research methods and design expertise for small clinical trials to be [...] Read more.
The explosion of knowledge concerning the interplay of genetic and environmental factors determining pathophysiology and guiding therapeutic choice has altered the landscape in pediatric clinical pharmacology and pharmacy. The need for innovative research methods and design expertise for small clinical trials to be undertaken in sparse populations has been accentuated. At the same time, shortfalls in critical human resources represent a key challenge, especially in low- and middle-income countries where the need for new research and education directions is greatest. Unless a specific action plan is urgently developed, there will be a continuing gap in availability of the essential expertise needed to address treatment challenges in special patient populations such as neonates, patients suffering from rare or neglected diseases, and children of all ages. Full article
1011 KiB  
Article
Placebo by Proxy in Neonatal Randomized Controlled Trials: Does It Matter?
by Tiziana L. Burkart, Andrea Kraus, Brigitte Koller, Giancarlo Natalucci, Beatrice Latal, Jean-Claude Fauchère, Hans Ulrich Bucher, Christoph M. Rüegger and For the Swiss EPO Neuroprotection Trial Group
Children 2017, 4(6), 43; https://doi.org/10.3390/children4060043 - 30 May 2017
Cited by 3 | Viewed by 6834
Abstract
Placebo effects emerging from the expectations of relatives, also known as placebo by proxy, have seldom been explored. The aim of this study was to investigate whether in a randomized controlled trial (RCT) there is a clinically relevant difference in long-term outcome between [...] Read more.
Placebo effects emerging from the expectations of relatives, also known as placebo by proxy, have seldom been explored. The aim of this study was to investigate whether in a randomized controlled trial (RCT) there is a clinically relevant difference in long-term outcome between very preterm infants whose parents assume that verum (PAV) had been administered and very preterm infants whose parents assume that placebo (PAP) had been administered. The difference between the PAV and PAP infants with respect to the primary outcome–IQ at 5 years of age–was considered clinically irrelevant if the confidence interval (CI) for the mean difference resided within our pre-specified ±5-point equivalence margins. When adjusted for the effects of verum/placebo, socioeconomic status (SES), head circumference and sepsis, the CI was [−3.04, 5.67] points in favor of the PAV group. Consequently, our study did not show equivalence between the PAV and PAP groups, with respect to the pre-specified margins of equivalence. Therefore, our findings suggest that there is a small, but clinically irrelevant degree to which a preterm infant’s response to therapy is affected by its parents’ expectations, however, additional large-scale studies are needed to confirm this conjecture. Full article
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192 KiB  
Commentary
The Development of Urease Inhibitors: What Opportunities Exist for Better Treatment of Helicobacter pylori Infection in Children?
by Sherif T. S. Hassan and Miroslava Šudomová
Children 2017, 4(1), 2; https://doi.org/10.3390/children4010002 - 04 Jan 2017
Cited by 30 | Viewed by 5792
Abstract
Stomach infection with Helicobacter pylori (H. pylori) causes severe gastroduodenal diseases in a large number of patients worldwide. The H. pylori infection breaks up in early childhood, persists lifelong if not treated, and is associated with chronic gastritis and an increased risk [...] Read more.
Stomach infection with Helicobacter pylori (H. pylori) causes severe gastroduodenal diseases in a large number of patients worldwide. The H. pylori infection breaks up in early childhood, persists lifelong if not treated, and is associated with chronic gastritis and an increased risk of peptic ulcers and gastric cancer. In recent years, the problem of drug-resistant strains has become a global concern that makes the treatment more complicated and the infection persistent at higher levels when the antibiotic treatment is stopped. Such problems have led to the development of new strategies to eradicate an H. pylori infection. Currently, one of the most important strategies for the treatment of H. pylori infection is the use of urease inhibitors. Despite the fact that large numbers of molecules have been shown to exert potent inhibitory activity against H. pylori urease, most of them were prevented from being used in vivo and in clinical trials due to their hydrolytic instability, toxicity, and appearance of undesirable side effects. Therefore, it is crucial to focus attention on the available opportunities for the development of urease inhibitors with suitable pharmacokinetics, high hydrolytic stability, and free toxicological profiles. In this commentary, we aim to afford an outline on the current status of the use of urease inhibitors in the treatment of an H. pylori infection, and to discuss the possibility of their development as effective drugs in clinical trials. Full article

2015

Jump to: 2023, 2020, 2017

1262 KiB  
Concept Paper
The Undiagnosed Diseases Program Integrated Collaboration System (UDPICS): One Program’s Experience Developing Custom Software to Support Research for Complex-Disease Families
by Jessica Guzman, Elizabeth Lee, David Draper, Zaheer Valivullah, Guoyun Yu, Murat Sincan, William A. Gahl and David R. Adams
Children 2015, 2(3), 342-357; https://doi.org/10.3390/children2030342 - 31 Jul 2015
Cited by 2 | Viewed by 6002
Abstract
The Undiagnosed Diseases Program (UDP) was started in 2008 with the goals of making diagnoses and facilitating related translational research. The individuals and families seen by the UDP are often unique and medically complex. Approximately 40% of UDP cases are pediatric. The Undiagnosed [...] Read more.
The Undiagnosed Diseases Program (UDP) was started in 2008 with the goals of making diagnoses and facilitating related translational research. The individuals and families seen by the UDP are often unique and medically complex. Approximately 40% of UDP cases are pediatric. The Undiagnosed Diseases Program Integrated Collaboration System (UDPICS) was designed to create a collaborative workspace for researchers, clinicians and families. We describe our progress in developing the system to date, focusing on design rationale, challenges and issues that are likely to be common in the development of similar systems in the future. Full article
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304 KiB  
Review
Challenges in Treating Low Blood Pressure in Preterm Infants
by Eugene M. Dempsey
Children 2015, 2(2), 272-288; https://doi.org/10.3390/children2020272 - 15 Jun 2015
Cited by 11 | Viewed by 6465
Abstract
Whilst the prevalence of low blood pressure in preterm infants seems to have fallen over the last number of years, the problem is still frequently encountered in the neonatal intensive care unit and many babies continue to receive intervention. Great variability in practice [...] Read more.
Whilst the prevalence of low blood pressure in preterm infants seems to have fallen over the last number of years, the problem is still frequently encountered in the neonatal intensive care unit and many babies continue to receive intervention. Great variability in practice persists, with a significant number of extremely low gestational age newborns in some institutions receiving some form of intervention, and in other units substantially less. A great degree of this variability relates to the actual criteria used to define hypotension, with some using blood pressure values alone to direct therapy and others using a combination of clinical, biochemical and echocardiography findings. The choice of intervention remains unresolved with the majority of centres continuing to administer volume followed by dopamine as a first line inotrope/vasopressor agent. Despite over 40 years of use there is little evidence that dopamine is of benefit both in the short term and long-term. Long-term follow up is available in only two randomised trials, which included a total of 99 babies. An under recognized problem relates to the administration of inotrope infusions in very preterm infants. There are no pediatric specific inotrope formulations available and so risks of errors in preparation and administration remain. This manuscript outlines these challenges and proposes some potential solutions. Full article
396 KiB  
Review
Influence of Food on Paediatric Gastrointestinal Drug Absorption Following Oral Administration: A Review
by Hannah K. Batchelor
Children 2015, 2(2), 244-271; https://doi.org/10.3390/children2020244 - 09 Jun 2015
Cited by 32 | Viewed by 11163
Abstract
The objective of this paper was to review existing information regarding food effects on drug absorption within paediatric populations. Mechanisms that underpin food–drug interactions were examined to consider potential differences between adult and paediatric populations, to provide insights into how this may alter [...] Read more.
The objective of this paper was to review existing information regarding food effects on drug absorption within paediatric populations. Mechanisms that underpin food–drug interactions were examined to consider potential differences between adult and paediatric populations, to provide insights into how this may alter the pharmacokinetic profile in a child. Relevant literature was searched to retrieve information on food–drug interaction studies undertaken on: (i) paediatric oral drug formulations; and (ii) within paediatric populations. The applicability of existing methodology to predict food effects in adult populations was evaluated with respect to paediatric populations where clinical data was available. Several differences in physiology, anatomy and the composition of food consumed within a paediatric population are likely to lead to food–drug interactions that cannot be predicted based on adult studies. Existing methods to predict food effects cannot be directly extrapolated to allow predictions within paediatric populations. Development of systematic methods and guidelines is needed to address the general lack of information on examining food–drug interactions within paediatric populations. Full article
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Graphical abstract

256 KiB  
Review
A New Ethical Challenge for Institutional Review Boards (IRBs)/Ethics Committees (ECs) in the Assessment of Pediatric Clinical Trials
by Klaus Rose and Hans Kummer
Children 2015, 2(2), 198-210; https://doi.org/10.3390/children2020198 - 28 May 2015
Cited by 13 | Viewed by 6162
Abstract
Both the US and EU have introduced pediatric pharmaceutical legislation to facilitate clinical trials in children and development of better medicines for children. The first concerns were published in 2014 that the European Medicines Agency (EMA)’s Pediatric Committee (PDCO) may be over-enthusiastic and [...] Read more.
Both the US and EU have introduced pediatric pharmaceutical legislation to facilitate clinical trials in children and development of better medicines for children. The first concerns were published in 2014 that the European Medicines Agency (EMA)’s Pediatric Committee (PDCO) may be over-enthusiastic and has compelled questionable pediatric clinical trials from pharmaceutical companies. Numerous clinical trials are mandated in rare conditions for which not enough patients exist for even one trial. Furthermore, where these trials are mandated in adolescent patients, the legal age limit of the 18th birthday is confused with a medical age limit and can result in separate clinical trials in adolescent patients that neither make medical nor scientific sense nor will ever recruit enough patients for a meaningful outcome. To confirm our concerns we searched the registry clinicaltrials.gov and found examples for PDCO-triggered unethical trials. We conclude that such trials should not be accepted by institutional review boards (IRBs)/ethics committees (ECs) and that clinical trials resulting from negotiations with EMA’s PDCO need extra careful scrutiny by IRBs/ECs in order to prevent unethical studies and damage to pediatric research and unnecessary risks to pediatric patients. Full article
214 KiB  
Review
Safety of Excipients in Pediatric Formulations—A Call for Toxicity Studies in Juvenile Animals?
by Georg Schmitt
Children 2015, 2(2), 191-197; https://doi.org/10.3390/children2020191 - 15 May 2015
Cited by 18 | Viewed by 8348
Abstract
The development of drug products for pediatric use often requires age-appropriate formulations which can be more complex and may involve a broader range of excipients than adult dosage forms. Excipients established for adult use are not always appropriate for use in children because [...] Read more.
The development of drug products for pediatric use often requires age-appropriate formulations which can be more complex and may involve a broader range of excipients than adult dosage forms. Excipients established for adult use are not always appropriate for use in children because they can affect children differently than adults. Therefore, a comprehensive safety assessment of the excipients in a pediatric formulation is essential before use, referring to existing safety data from adult human and animals as well as safety data from pediatric use and juvenile toxicity studies, when available. The overall risk assessment needs to consider the safety risk from the excipients and the extent to which the risk from the disease as such will be ameliorated by the drug formulation. Non-clinical safety studies in juvenile animals are used to assess for specific toxicities or sensitivities of excipients and for establishing safe exposures in pediatric age groups. As for any active ingredient, non-clinical safety studies in juvenile animals should only be performed for excipients if important for clinical risk assessment and labelling. Pharmaceutical companies should be critical of excessive demands for juvenile animal testing, particularly of excipients when critically needed for significant therapeutic benefit. Full article
552 KiB  
Review
Cystic Fibrosis Treatment: A Paradigm for New Pediatric Medicines, Globalization of Drug Development and the Role of the European Medicines Agency
by Klaus Rose and Michael G. Spigarelli
Children 2015, 2(1), 108-130; https://doi.org/10.3390/children2010108 - 23 Mar 2015
Cited by 3 | Viewed by 6284
Abstract
The European Pediatric Pharmaceutical Legislation wants children to benefit more from pharmaceutical progress. In rare diseases, concerns have been raised that this legislation might damage research and stymie drug development. We discuss the role of the European Medicines Agency (EMA) and its Pediatric [...] Read more.
The European Pediatric Pharmaceutical Legislation wants children to benefit more from pharmaceutical progress. In rare diseases, concerns have been raised that this legislation might damage research and stymie drug development. We discuss the role of the European Medicines Agency (EMA) and its Pediatric Committee (PDCO) in the development of ivacaftor, first-in-class for cystic fibrosis (CF) patients with the G551D mutation (and eight other mutations later) and of lumacaftor and ataluren, two more potential break-through CF medications. Ivacaftor was USA-approved early 2012 and six months later in the EU. Registration was based on the same data. We analyzed these drugs’ EU pediatric investigation plans (PIPs) and compared the PIP-studies with the pediatric CF studies listed in www.clinicaltrials.gov. The ivacaftor PIP studies appear to reflect what the developer planned anyway, apart from a study in 1–23-month-olds, which has not yet started. The total negotiation time for the current PIP version was approximately 5.5 years. For companies that develop drugs in pediatric diseases, e.g., CF, PIPs represent considerable additional procedural workload with minimal or no additional benefit for the patients. New drugs for pediatric diseases should not be hampered by additional, unnecessary and costly bureaucracy, but be registered as rapidly as possible without compromising safety. Full article
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