Pediatric Drug Development: Reviewing Challenges and Opportunities by Tracking Innovative Therapies

Abstract

The paradigm of pediatric drug development has been evolving in a "carrot-and-stick"-based tactic to address population-specific issues. However, the off-label prescription of adult medicines to pediatric patients remains a feature of clinical practice, which may compromise the age-appropriate evaluation of treatments. Therefore, the United States and the European Pediatric Formulation Initiative have recommended applying nanotechnology-based delivery systems to tackle some of these challenges, particularly applying inorganic, polymeric, and lipid-based nanoparticles. Connected with these, advanced therapy medicinal products (ATMPs) have also been highlighted, with optimistic perspectives for the pediatric population. Despite the results achieved using these innovative therapies, a workforce that congregates pediatric patients and/or caregivers, healthcare stakeholders, drug developers, and physicians continues to be of utmost relevance to promote standardized guidelines for pediatric drug development, enabling a fast lab-to-clinical translation. Therefore, taking into consideration the significance of this topic, this work aims to compile the current landscape of pediatric drug development by (1) outlining the historic regulatory panorama, (2) summarizing the challenges in the development of pediatric drug formulation, and (3) delineating the advantages/disadvantages of using innovative approaches, such as nanomedicines and ATMPs in pediatrics. Moreover, some attention will be given to the role of pharmaceutical technologists and developers in conceiving pediatric medicines.

Keywords: cell- and tissue-based therapy; gene therapy; nanoparticles; pediatrics.

Figure 1

Infographic of the age categorization of pediatric patients according to the International Council for Harmonization (ICH) guideline E11(R1). As summarized, there is considerable heterogeneity in developmental categorization (e.g., physical, cognitive, and psychosocial) across pediatric ages [2]. Central nervous system (CNS), blood–brain barrier (BBB), increase (↑).

Figure 2

A summary of the factors impacting pharmacotherapy practice and the development of therapeutics aimed at pediatric patients.

Figure 3

Infographic of the pharmaceutical pipeline and clinical trials timeline. In brief, a screening of potential drug candidates is performed during the drug discovery and development (D&D) step, which takes an average time of five years. The most promising compounds go further to pre-clinical trials under good laboratory practices (GLP), with a possible bridge to the clinical phase by taking advantage of the first-in-human trials (Phase 0), with interesting feedback on dosing and toxicity levels of the most promising candidate, which takes 18 months on average. As part of the investigational new drug (IND) portfolio, the clinical trials can go further, and if the treatment is effective and safe for human use the new drug application (NDA) obtains the approval of the regulatory agency (FDA). After, the pharmacovigilance post-marketing safety and efficacy studies are conducted over time [32,33]. High throughput screening (HTS).

Figure 4

Historical roadmap of the regulation and guidelines developed for clinical studies related to the pediatric population in China, the European Union (EU), and the United States (US) [28,39,40,41,42].

Figure 5

Overview of the granted projects (green bars) and the financial support (blue line) sponsored by the National Institutes of Health (NIH) that address the pediatric population, between 2000 and 2 August 2023 [52].

Figure 6

Summary of pharmacokinetic differences in the pediatric population compared with adults [69]. Area under the curve (AUC); maximum concentration (C_max); volume of distribution (V_d); increase (↑); decrease (↓).

Figure 7

Summary of the different types of nanoparticles that can be used in nanomedicine.

Figure 8

Structural representation of some natural, semi-synthetic, and synthetic polymers.

Figure 9

(A) Schematic representation and (B) delivery procedure of the angiopep-2-PEG-doxorubicin-gold nanoparticles (An-PEG-DOX-AuNPs). Briefly, the LRP1 receptor could mediate An-PEG-DOX-AuNP penetration through the BBB and targeting to glioma cells, after which DOX would be released at the tumor site or in tumor cells and enter into nuclei to induce tumor cell apoptosis. Reprinted from [207], copyright (2014), with permission from Elsevier.

Figure 10

Summary of some issues that remain in developing nanotherapies for pediatric patients.

Figure 11

Schematic summary of the current available advanced therapy medicinal products (ATMPs).

Figure 12

Regulatory framework followed by EMA for marketing authorization of ATMPs in the European Union. Reprinted from [212], under a CC BY 4.0 license.