Development Of Paediatric Medicines Research Articles

Public health relevance of medicines developed under paediatric legislation in Europe and the USA: a systematic mapping study

BackgroundLegislation in the European Union (EU) and the USA promoting the development of paediatric medicines has contributed to new treatments for children. This study explores how such legislation responds to...

Real-world data for the availability of pediatric medicines in Chinese hospitals: a multi-center survey and analysis.

Aim: No information exists on the availability of pediatric medicines in China. This study aimed to access the availability of different types of pediatric medicine and determine their ratio in medical institution drug catalogs. Methods: Based on drug instructions, an expert meeting method was used to divide pediatric medicines into five categories: child-specific medicine (CSM), co-use medicine for adults and children (CMAC), other pediatric medicines (OCM), off-label medicine use (OMU), and non-child medicine (NM). Results: A total of 60 hospitals nationwide participated in this survey, namely, 20 children's hospitals (C-hosp), 14 maternal and child healthcare hospitals (MCHC-hosp), and 26 general hospitals (G-hosp). The average number of drug catalogs in G-hosp was significantly higher than that in C-hosp and MCHC-hosp. CSM accounted for 9.77% of the C-hosp catalog, 7.12% of the MCHC-hosp catalog, and 1% of the G-hosp catalog. The availability rate of CMAC was 49.63% in C-hosp and 40.87% and 31% in MCHC-hosp and G-hosp, respectively. The proportion of OCM in C-hosp (27.28%) was higher than that in MCHC-hosp (13.4%) and G-hosp (5%). The OMU occupied ratio in C-hosp, MCHC-hosp, and G-hosp is not negligible, which was 12.06%, 8.7%, and 10% respectively. The proportion of NM in C-hosp was almost negligible but was 29.91% and 53% in MCHC-hosp and G-hosp, respectively. Compared to the CSM and CMAC listed in China, the share of CSM in C-hosp was close to 40%, which was much higher than that of G-hosp and MCHC-hosp. In contrast, the share of CMAC in G-hosp was nearly 30%, which was significantly higher than that in C-hosp and MCHC-hosp. Health insurance covers most of these five types of pediatric medicines, with the proportion of insured medicines reaching close to 80% in C-hosp and approximately 85% in MCHC-hosp and G-hosp. Discussion: The availability of specific medicines suitable for use in children is generally low, and even CSM in specialized hospitals such as C-hosp cannot meet the relatively high accessibility level of WHO evaluation standards. Policies and measures should be implemented to boost the research and development of pediatric medicines, as well as supplement safety information lacking in instruction manuals.

Young patients’ involvement in a composite endpoint method development on acceptability for paediatric oral dosage forms

BackgroundIn line with the European Paediatric Regulation, the European Medicines Agency (EMA) asks for investigation of a medicine’s acceptability in paediatric medicines development. A standardised acceptability testing method combining the outcome of “swallowability” and “palatability” assessments to a “composite endpoint on acceptability” was recently developed. Before this method’s suitability for selection of the most acceptable drug formulation of a new medicine for children can be broadly recommended, the acceptance and relevance of such established acceptability needs the critical review and input from young patients with understanding of the medicines development methodology. The benefit of involving patients in drug product development, clinical research and innovation is well established.MethodsDuring a focus group meeting with the KIDS Barcelona (young people advisory group, age 16–23 years) the suitability of the “composite endpoint on acceptability” methodology was assessed. Via electronic questionnaires the importance of involving patients in the medicines development and in the acceptability method development was investigated. Questions on how best to determine palatability and swallowability were asked. The relevance of all EMA-listed acceptability elements was assessed via coloured and numbered stickers and questionnaires.ResultsThe results showed that the involvement of young people in the medicines and acceptability method development was rated high. The group worked out that a 5-point smiley Likert Scale is preferred for assessing acceptability by 6–11 year old patients, while a Visual Analogue Scale is preferred for collecting adolescents’ opinion. The ranking of the EMA-listed acceptability elements showed that palatability and swallowability are the most relevant parameters, while colour of the medicine was rated as least relevant. These results, established face-to-face, were confirmed in a repeat of the ranking through an electronic questionnaire, completed by the participants individually and remotely, 5 weeks later.ConclusionThis work reinforced the need and value to involve young people in the medicines lifecycle, and specifically in this acceptability method development. As next step other focus group meetings with more young people from different European countries are planned.

HPR45 Analysis of Alternative Access Routes and Time to Access for Paediatric Indication Expansions with Consideration of Regulatory, Pricing, and Access Incentives

Many regulatory organisations provide incentives for the development of paediatric medicines. Data generation in paediatric indications, and even more so orphan paediatric indications, is challenging and as such pharmaceutical manufacturers face evidence and consequently price and access challenges when expanding into these indications. This study aims to evaluate routes of access and time to access for paediatric indication expansions in Germany, France, Italy, Spain, UK, Canada, Japan, and China.

Development of Paediatric Medicines: Key Risk Factors and Non-clinical Research Programmes

The lack of approved paediatric medicines is a global problem. Since paediatric patients are a high-risk group, a developer of paediatric medicines needs to evaluate and minimise unjustified risks early in the development process.The aim of the study was to analyse the current regulatory and methodological framework for non-clinical research and identify key risk factors that need addressing in paediatric drug development in order to substantiate the safety of children. One of the main objectives of non-clinical safety assessment of a medicinal product intended for children is to identify undesirable effects on child growth and development. According to national and international methodological guidelines, the developer may obtain the most valuable information to decide whether it is safe to enrol children into a clinical trial from the safety data collected in clinical studies in adult subjects. If the safety data available from studies in mature animals and adult subjects are insufficient to evaluate the safety of the clinical trial for paediatric patients, the developer may consider conducting non-clinical studies in immature (juvenile) animals. A paediatric non-clinical testing programme should be in line with a comprehensive significance assessment of key risk factors carried out on a case-by-case basis using weight-of-evidence (WoE) analysis. The conclusion on the safety of a medicinal product for children should be based on risk assessment in relevant clinical and non-clinical studies.

Advancing evidence-based treatment of infectious diseases in children with real-world data: Opportunities and challenges.

There is an increased interest in utilizing real-world data (RWD) for pharmaceutical research and regulatory decision-making. The development and use of pediatric medicines could benefit greatly from real-world data studies given nearly half of drugs prescribed to children are "off-label", meaning there is a lack of pediatric-specific evidence from controlled trials, while there is an abundance of data from routine clinical practice. Currently, the use of real-world data, such as data from electronic health records, is lacking in pediatric research, especially within infectious diseases. Here, we discuss opportunities and challenges for real-world data to generate evidence on the optimal treatment and management of infectious diseases in children.

Acceptability of Prednisolone in an Open-Label Randomised Cross-Over Study-Focus on Formulation in Children.

Developing acceptable medicines for children is a complicated task. Several factors must be considered, including age, physiology, texture preference, formulation, and legal framework among others. In the development of new paediatric medicines, these factors are assessed. However, for older medicines, e.g., prednisolone, acceptability is still a challenge. This study was an open-label randomised three-arm cross-over study investigating different formulations of prednisolone (crushed tablets, whole tablets, and oral solution) in paediatric patients with asthma and asthma-like symptoms. Participants were randomised into two different formulations on two consecutive days. For each formulation, the child or caregiver was asked to evaluate acceptability using a modified five-point Wong Baker Face scale. An analysis of variance (ANOVA) model was used to test for significance. For the 41 children, included mean age was 4.7 years (SD ± 3.6), and mean weight was 21 kg (SD ± 10.8). Sixty-one percent were boys. The participants were divided accordingly into three age groups: 6 to 23 months (N = 11), 2 to 5 years (N = 14), and 6–11 years (N = 16). The overall acceptability was low, with only 23 out of 71 scores rating the treatment either 1 or 2 (32%). The ANOVA test showed a significant difference in acceptability score between crushed tablets and whole tablets (p < 0.003). The mean acceptability score for the crushed tablet was the least favourable at 3.9 compared to oral solution (3.1), oro-dispersible tablet (2.8), and whole tablets (2.4). This is problematic in long-term treatment and for the youngest children who cannot swallow tablets. The improvement of age-appropriate and acceptable formulations is necessary.

Considerations for and against dosing rodent pups before 7 days of age in juvenile toxicology studies

This review focuses on preweaning ontogenic and developmental processes that can influence the selection of the appropriate age at which to start dosing rodent pups in juvenile animal studies (JAS). The ICH S11 guideline on ‘Nonclinical Safety Testing in Support of Development of Paediatric Medicines’ highlights the need to adapt the age from which animals are dosed according to the stage of development in the target organs/tissues of concern in the youngest pediatric patients. Rodents (rat or mouse) are the most common species for JAS. Despite previous practices, based on comparative ontogeny, it is rarely necessary to dose rodents younger than one week of age since postnatal day (PND)7 is appropriate to address concern for the vast majority of organs. In exceptional cases, earlier dosing (e.g., PND4) can be appropriate to address specific concern in preterm neonates and when a tissue of concern has a particularly early developmental trajectory in the rodent compared to humans. The comparative development of the CNS is particularly complex. While exposure of rodents from PND10 covers most CNS development stages relevant to human neonates, a later dosing start (yet, not later than PND14) can sometimes be appropriate to reflect specific aspects (e.g., transformation of GABAergic transmission). An extended study design including subsets of several ages can be helpful to address multiple concerns within a preweaning JAS. Such design can allow for individual assessment of each concern, whilst minimizing (potentially irrelevant) signals from tissues exposed at a developmental stage that do not match the human situation.

Regulatory Perspectives on Juvenile Animal Toxicologic Pathology.

The Society of Toxicologic Pathology's Annual Virtual Symposium (2021) included a session on "Regulatory Perspectives on Juvenile Animal Toxicologic Pathology." The following narrative summarizes the key concepts from the four talks included in this symposium session chaired by Drs Deepa Rao and Alan Hoberman. These encompass an overview of various global regulations impacting the conduct of juvenile animal studies in pharmaceutical drug development and chemical toxicity assessments in a talk by Dr Alan Hoberman. Given the numerous regulatory guidances and legal statutes that have covered the conduct of juvenile animal studies and the recent harmonization of these guidances for pharmaceuticals, Dr Paul Brown provided an update on the harmonization of these guidances for pharmaceuticals, in the recently finalized version of the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use S11 guidance document, "Nonclinical Safety Testing in Support of Development of Pediatric Medicines." The first two talks on regulations were followed by two talks focused on an evaluation of the postnatal development of two major organ systems relevant in juvenile animals. Dr Aurore Varela covered study design and endpoints impacting the skeletal system (bone), while Dr Brad Bolon presented a talk on the study design and conduct of neuropathology evaluations for the developing nervous system.

The Minipig – A Rising Star for Nonclinical Safety Testing in Support of Development of Paediatric Medicines?

The Minipig – A Rising Star for Nonclinical Safety Testing in Support of Development of Paediatric Medicines?

Path towards efficient paediatric formulation development based on partnering with clinical pharmacologists and clinicians, a conect4children expert group white paper.

Improved global access to novel age-appropriate formulations for paediatric subsets, either of new chemical entities or existing drugs, is a priority to ensure that medicines meet the needs of these patients. However, despite regulatory incentives, the introduction to the market of paediatric formulations still lags behind adult products. This is mainly caused by additional complexities associated with the development of acceptable age-appropriate paediatric medicines. This position paper recommends the use of a paediatric Quality Target Product Profile as an efficient tool to facilitate early planning and decision making across all teams involved in paediatric formulation development during the children-centric formulation design for new chemical entities, or to repurpose/reformulate off-patent drugs. Essential key attributes of a paediatric formulation are suggested and described. Moreover, greater collaboration between formulation experts and clinical colleagues, including healthcare professionals, is advocated to lead to safe and effective, age-appropriate medicinal products. Acceptability testing should be a secondary endpoint in paediatric clinical trials to ensure postmarketing adherence is not compromised by a lack of acceptability. Not knowing the indications and the related age groups and potential dosing regimens early enough is still a major hurdle for efficient paediatric formulation development; however, the proposed paediatric Quality Target Product Profile could be a valuable collaborative tool for planning and decision making to expedite paediatric product development, particularly for those with limited experience in developing a paediatric product.

Polymeric and Lipid Nanoparticles: Which Applications in Pediatrics?

This review aims to provide the state of the art on polymeric and lipid nanoparticles, used or suggested to approach pediatric diseases’ problems and needs, and to inspire new researches in this field. Several drugs are currently not available in formulations suitable for pediatric patients. The United States Pediatric Formulation Initiative suggested applying new technologies to pediatric drug formulations, for instance, nanotechnology. The literature analysis showed that polymeric and lipid nanoparticles have been widely studied to treat pediatric diseases, and albumin nanoparticles and liposomes are already used in clinical practice. Nevertheless, these studies are focused almost exclusively on pediatric cancer treatment. Although nanomedicine may solve many needs of pediatric diseases and medicines, the unavailability of data on pharmacokinetics, safety and efficacy of both drugs and nanoparticles in pediatric patients limits the development of new pediatric medicines based on nanoparticles. Therefore, nanomedicine applied in pediatrics remains a significant challenge in the near future.

Paediatric Medicines in Europe: The Paediatric Regulation-Is It Time for Reform?

Objectives: In this paper, we investigated the effects of the European Paediatric Regulation (EC) N° 1901/2006 with respect to satisfying the paediatric therapeutic needs, assessed in terms of the increased number of paediatric medicinal products, new therapeutic indications in specific high-need conditions (neonates, oncology, rare disease, etc.) and increased number of paediatric clinical studies supporting the marketing authorisation.Methods: We analysed the paediatric medicinal products approved by the European Medicines Agency in the period January 2007-December 2019, by collecting the following data: year of approval, active substance, legal basis for the marketing authorisation, type of medicinal product (i.e., chemical, biological, or ATMP), orphan drug status, paediatric indication, Anatomical Therapeutic Chemical code (first-level), number and type of paediatric studies. Data were compared with similar data collected in the period 1996–2006.Results: In the period January 1996–December 2019, in a total of 1,190 medicinal products and 843 active substances, 34 and 38%, respectively, were paediatric. In the two periods, before and after the Paediatric Regulation implementation, the paediatric/total medicinal products ratio was constant while the paediatric/total active substances ratio decreased. Moreover, excluding generics and biosimilars, a total of 106 and 175 paediatric medicines were granted a new paediatric indication, dosage or age group in the two periods; out of 175, 128 paediatric medicines had an approved Paediatric Investigational Plan. The remaining 47 were approved without an approved Paediatric Investigational Plan, following the provisions of Directive 2001/83/EC and repurposing an off-patent drug. The analysis of the clinical studies revealed that drugs with a Paediatric Investigational Plan were supported by 3.5 studies/drug while drugs without a Paediatric Investigational Plan were supported by only 1.6 studies/drug.Discussion: This report confirms that the expectations of the European Paediatric Regulation (EC) N° 1901/2006 have been mainly satisfied. However, the reasons for the limited development of paediatric medicines in Europe, should be further discussed, taking advantage of recent initiatives in the regulatory field, such as the Action Plan on Paediatrics, and the open consultation on EU Pharmaceutical Strategy.

A National US Survey of Pediatric Emergency Department Coronavirus Pandemic Preparedness.

ObjectiveWe aim to describe the current coronavirus disease 2019 (COVID-19) preparedness efforts among a diverse set of pediatric emergency departments (PEDs) within the United States.MethodsWe conducted a prospective multicenter survey of PED medical director(s) from selected children’s hospitals recruited through a long established national research network. The questionnaire was developed by physicians with expertise in pediatric emergency medicine, disaster readiness, human factors, and survey development. Thirty-five children’s hospitals were identified for recruitment through an established national research network.ResultsWe report on survey responses from 25 (71%) of 35 PEDs, of which 64% were located within academic children's hospitals. All PEDs witnessed decreases in non–COVID-19 patients, 60% had COVID-19–dedicated units, and 32% changed their unit pediatric patient age to include adult patients. All PEDs implemented changes to their staffing model, with the most common change impacting their physician staffing (80%) and triaging model (76%). All PEDs conducted training for appropriate donning and doffing of personal protective equipment (PPE), and 62% reported shortages in PPE. The majority implemented changes in the airway management protocols (84%) and cardiac arrest management in COVID patients (76%). The most common training modalities were video/teleconference (84%) and simulation-based training (72%). The most common learning objectives were team dynamics (60%), and PPE and individual procedural skills (56%).ConclusionsThis national survey provides insight into PED preparedness efforts, training innovations, and practice changes implemented during the start of COVID-19 pandemic. Pediatric emergency departments implemented broad strategies including modifications to staffing, workflow, and clinical practice while using video/teleconference and simulation as preferred training modalities. Further research is needed to advance the level of preparedness and support deep learning about which preparedness actions were effective for future pandemics.

Dose range finding approach for rodent preweaning juvenile animal studies.

Strategies for conducting juvenile dose ranging studies before definitive toxicity juvenile animal studies (JAS) have evolved, but the aim of demonstrating study design robustness and efficient animal use remains the same. The objective of dose selection is to identify a strategy to achieve consistent systemic exposure for the duration of the JAS while maintaining exposure separation between dose groups. For preweaning rodents this can prove challenging, as these studies typically treat animals over a broad period of considerable organ development. In our experience, over 45 rodent juvenile studies (dose range, definitive or investigative) were conducted over 20 years to support pediatric medicine development. In most cases (86%, 12/14), preweaning rodents required decreased doses of test articles than adult rodents; the majority (83%, 10/12) were due to increased systemic exposures in immature animals at the same doses. Thus, extrapolating tolerability and exposure data from adults is not ideal and should not take the place of well-designed juvenile dose range studies. We propose a phased dose-range-finding approach by first conducting a tolerability phase with a few animals at a starting age corresponding to the youngest clinical starting age, spanning a wide range of doses, then a dose range phase with larger group sizes and fewer doses; both phases incorporate toxicokinetics. Often, exposure was higher in preweaning animals and decreased as animals matured postweaning (postnatal day, PND 21 and older), supporting an age-based dose adjustment strategy. Case studies demonstrate dose adjustment approaches incorporating dose increases or decreases or changes in dose frequency.

Cardiovascular Paediatric Medicines Development: Have Paediatric Investigation Plans Lost Heart?

This work aimed to establish whether paediatric needs in cardiovascular diseases have been met by paediatric investigation plans (PIPs) produced since the development of the European Union Paediatric Regulation in 2007. The European Medicines Agency repository was searched for patterns in the development of paediatric medicines in general. Next, positive PIPs related to cardiovascular diseases were scrutinized for outcomes and compared to specific paediatric cardiovascular needs. In total, 1866 PIPs were identified with 12% corresponding to decisions taken for cardiovascular medicines. However, despite this therapeutic area having the greatest number of overall PIPs, only 14% of established needs in paediatric cardiovascular diseases were addressed by PIPs with positive decisions. Further, 71.9% of PIPs with decisions in cardiovascular disease corresponded to full waivers, so the product would not be studied in paediatrics. Despite the progress found in overall numbers of PIPs published, cardiovascular products are still commonly used off-label in paediatrics. Particularly, there is a need to develop products to treat heart failure and hypertension, two areas with clear unmet clinical needs in paediatrics. A case study on valsartan showed that industry, regulators, health technology assessment bodies, and prescribers should work together to reduce off-label use of paediatric cardiovascular diseases (CVD).

In Vivo Predictive Dissolution Testing of Montelukast Sodium Formulations Administered with Drinks and Soft Foods to Infants

In vitro dissolution testing conditions that reflect and predict in vivo drug product performance are advantageous, especially for the development of paediatric medicines, as clinical testing in this population is hindered by ethical and technical considerations. The aim of this study was to develop an in vivo predictive dissolution test in order to investigate the impact of medicine co-administration with soft food and drinks on the dissolution performance of a poorly soluble compound. Relevant in vitro dissolution conditions simulating the in vivo gastrointestinal environment of infants were used to establish in vitro-in vivo relationships with corresponding in vivo data. Dissolution studies of montelukast formulations were conducted with mini-paddle apparatus on a two-stage approach: infant fasted-state simulated gastric fluid (Pi-FaSSGF; for 1 h) followed by either infant fasted-state or infant fed-state simulated intestinal fluid (FaSSIF-V2 or Pi-FeSSIF, respectively; for 3 h). The dosing scenarios tested reflected in vivo paediatric administration practices: (i.) direct administration of formulation; (ii.) formulation co-administered with vehicles (formula, milk or applesauce). Drug dissolution was significantly affected by co-administration of the formulation with vehicles compared with after direct administration of the formulation. Montelukast dissolution from the granules was significantly higher under fed-state simulated intestinal conditions in comparison with the fasted state and was predictive of the in vivo performance when the granules are co-administered with milk. This study supports the potential utility of the in vitro biorelevant dissolution approach proposed to predict in vivo formulation performance after co-administration with vehicles, in the paediatric population.

That daily trickle of death: Infant mortality and the dawn of pediatric medicine in the province of Santiago, Chile, 1870-1913

This article deals with the problem of infant mortality in Santiago, Chile, and the development of pediatric medicine during the second half of the nineteenth century and the beginning of the twentieth century. Emphasis is placed on the specialists who contributed to organizing the knowledge and practices that structured their professional field. In order to pursue the objective and systematize this new medical field, our analysis suggests the decisive role of the establishment of the Faculty of Medicine and the appearance of coursework dedicated specifically to childhood diseases. Our research is based on various historical sources including the press, medical literature, thesis archives, and the Anuario Estadístico de la República de Chile [Statistical Yearbook of the Republic of Chile]. Likewise, the inauguration of children's hospitals expresses an institutional setting where physicians position their work, put scientific treatments into practice, and most importantly, they become spaces that allow for the reduction of infant mortality.

Availability of Authorizations from EMA and FDA for Age-Appropriate Medicines Contained in the WHO Essential Medicines List for Children 2019.

Lack of age-appropriate commercially drug products availability is a common problem in pediatric therapeutics; this population needs improved and safer drug delivery. In addition, biopharmaceutic aspects, dosage requirements, and swallowing abilities demand pediatric forms different to adult formulations. The objective of this study was to evaluate the authorization availability from United States Food and Drug Administration (FDA) and European Medicines Agency (EMA) of oral essential medicines for children and analyze its age-appropriateness for oral administration in children. All oral drugs from 7th List of Essential Medicines for Children by World Health Organization (WHO) were selected. Availability of commercial drug products was collected from OrangeBook, Spanish drug product catalogue, British electronic Medicines Compendium, and the International Vademecum. Tablets, effervescent tablets, and capsules were considered as not age-appropriate forms. Liquid forms, powder for oral suspension, mini tablets, granules, and soluble films were considered as age-appropriate forms due to their flexibility. More than 80% of the studied drugs possess a commercial authorization in oral forms in both EMA and FDA. Nevertheless, around 50% of these formulations are not age-appropriate for most pediatric groups. This study shows the lack of age-appropriate medicines for children. More efforts are needed to improve development and approval of pediatric medicines.

How is the Pharmaceutical Industry Structured to Optimize Pediatric Drug Development? Existing Pediatric Structure Models and Proposed Recommendations for Structural Enhancement

BackgroundPediatric regulations enacted in both Europe and the USA have disrupted the pharmaceutical industry, challenging business and drug development processes, and organizational structures. Over the last decade, with science and innovation evolving, industry has moved from a reactive to a proactive mode, investing in building appropriate structures and capabilities as part of their business strategy to better tackle the challenges and opportunities of pediatric drug development.MethodsThe EFGCP Children’s Medicines Working Party and the IQ Pediatric working group have joined their efforts to survey their member company representatives to understand how pharmaceutical companies are organized to fulfill their regulatory obligations and optimize their pediatric drug development programs.ResultsKey success factors and recommendations for a fit-for-purpose Pediatric Expert Group (PEG) were identified.ConclusionPediatric structures and expert groups were shown to be important to support optimization of the development of pediatric medicines.