Topical Collection "Development of Medicines for Paediatric and Rare Diseases"

Editors

Guest Editor
Prof. Dr. Jane Grant-Kels

Department of Dermatology, University of Connecticut Health Center, Farmington, CT 06030, USA
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Phone: 860-519-7008
Interests: melanoma; skin cancer; atypical nevi; reflectance confocal microscopy
Guest Editor
Dr. Klaus Rose

Klausrose Consulting, Aeussere Baselstrasse 308, 4125 Riehen, BS, Switzerland
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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
Guest Editor
Prof. Johannes N. Van den Anker

1. Department of Paediatric Pharmacology, Universitäts-Kinderspital beider Basel (UKBB, Spitalstrasse 33, CH-4031 Basel, Switzerland
2. Division of Clinical Pharmacology, Children's National Health System, 111 Michigan Avenue, N.W., Washington, D.C. 20010
3. Intensive Care and Department of Paediatric Surgery, Erasmus Medical Center – Sophia Children’s Hospital, Rotterdam, the Netherlands
Website | E-Mail
Interests: developmental pharmacology; neonatal pharmacology; paediatric pharmacology; neonatal medicine; neonatal infectious diseases; pharmacokinetics; pharmacodynamics; neonatal clinical trials

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 However, paediatric clinical practice has changed less than expected, and the initial enthusiasm has been replaced by a more realistic assessment.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

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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 (9 papers)

2017

Jump to: 2015

Open AccessCommentary Key Challenges in the Search for Innovative Drug Treatments for Special Populations. Converging Needs in Neonatology, Pediatrics, and Medical Genetics
Received: 29 June 2017 / Revised: 27 July 2017 / Accepted: 1 August 2017 / Published: 4 August 2017
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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
Open AccessArticle Placebo by Proxy in Neonatal Randomized Controlled Trials: Does It Matter?
Received: 13 April 2017 / Revised: 19 May 2017 / Accepted: 24 May 2017 / Published: 30 May 2017
Cited by 1 | PDF Full-text (1011 KB) | HTML Full-text | XML Full-text
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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Open AccessCommentary The Development of Urease Inhibitors: What Opportunities Exist for Better Treatment of Helicobacter pylori Infection in Children?
Received: 17 November 2016 / Revised: 25 December 2016 / Accepted: 27 December 2016 / Published: 4 January 2017
Cited by 6 | PDF Full-text (192 KB) | HTML Full-text | XML Full-text
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: 2017

Open AccessConcept Paper The Undiagnosed Diseases Program Integrated Collaboration System (UDPICS): One Program’s Experience Developing Custom Software to Support Research for Complex-Disease Families
Children 2015, 2(3), 342-357; https://doi.org/10.3390/children2030342
Received: 15 April 2015 / Revised: 11 July 2015 / Accepted: 14 July 2015 / Published: 31 July 2015
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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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Open AccessReview Challenges in Treating Low Blood Pressure in Preterm Infants
Children 2015, 2(2), 272-288; https://doi.org/10.3390/children2020272
Received: 10 April 2015 / Accepted: 5 June 2015 / Published: 15 June 2015
Cited by 1 | PDF Full-text (304 KB) | HTML Full-text | XML Full-text
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
Open AccessReview Influence of Food on Paediatric Gastrointestinal Drug Absorption Following Oral Administration: A Review
Children 2015, 2(2), 244-271; https://doi.org/10.3390/children2020244
Received: 30 March 2015 / Revised: 15 May 2015 / Accepted: 18 May 2015 / Published: 9 June 2015
Cited by 7 | PDF Full-text (396 KB) | HTML Full-text | XML Full-text
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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Open AccessReview A New Ethical Challenge for Institutional Review Boards (IRBs)/Ethics Committees (ECs) in the Assessment of Pediatric Clinical Trials
Children 2015, 2(2), 198-210; https://doi.org/10.3390/children2020198
Received: 27 March 2015 / Accepted: 19 May 2015 / Published: 28 May 2015
Cited by 9 | PDF Full-text (256 KB) | HTML Full-text | XML Full-text
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
Open AccessReview Safety of Excipients in Pediatric Formulations—A Call for Toxicity Studies in Juvenile Animals?
Children 2015, 2(2), 191-197; https://doi.org/10.3390/children2020191
Received: 3 March 2015 / Revised: 2 April 2015 / Accepted: 27 April 2015 / Published: 15 May 2015
Cited by 3 | PDF Full-text (214 KB) | HTML Full-text | XML Full-text
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
Open AccessReview Cystic Fibrosis Treatment: A Paradigm for New Pediatric Medicines, Globalization of Drug Development and the Role of the European Medicines Agency
Children 2015, 2(1), 108-130; https://doi.org/10.3390/children2010108
Received: 19 January 2015 / Revised: 10 March 2015 / Accepted: 11 March 2015 / Published: 23 March 2015
Cited by 1 | PDF Full-text (552 KB) | HTML Full-text | XML Full-text
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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