Pediatric Drug Development: Key Considerations and Challenges
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Pediatric medicines, often termed “age-appropriate” or “child-friendly”, are vital to the health and wellbeing of children. Nevertheless, a core principle in any pediatric drug development program is that “children should not be enrolled in a clinical study unless necessary to achieve an important pediatric public health need”.1 As such, the balance of risk and likely clinical benefits must be assessed and the child should not be adversely impacted by enrolment in the research study.
Regulatory agencies have attempted to incentivize, mandate and support the progression of “child-friendly” medications. The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) has recently updated ICH-E11(R1), which outlines “an approach to the safe, efficient, and ethical study of medicinal products in the pediatric population”.1 In Europe, the development of pediatric medicines is aimed at preventing children from undergoing unnecessary clinical investigations; facilitating research into pediatric medicines and pediatric dosage forms; and improving labeling of pediatric medicines. The European Medicines Agency (EMA) has introduced a Paediatric Investigation Plan (PIP), which is a prerequisite for all new pediatric products.2 The US Food and Drug Administration’s (FDA) pediatric exclusivity initiative provides for a six-month additional exclusivity or additional patent protection in return for initiating pediatric clinical studies.3 Subsequently, the Best Pharmaceuticals for Children Act (BPCA) established a procedure for the study of pediatric applications of generic drugs, to study pediatric applications of non-generic drugs where no pediatric medicines where available and endorsed the publication of all new findings.4
In certain cases, it is recognized that there will be intrinsic difficulties with generating data across a pediatric population due to a variety of ethical considerations and feasibility issues.1 Alternative approaches may provide opportunities to address these concerns. These include biopharmaceutical classification system modeling,5,6,7 pharmacokinetic–pharmacodynamic modeling,8 etc. Modeling can also be used for “clinical trial simulation, dose selection, choice and optimization of study design, endpoint selection and pediatric extrapolation”.1
“Children” are a very broad and heterogenous group, spanning the first two decades of life and sub-divided into five patient sub-classes. Pre-term, new-born infants, i.e., “premature”, full-term new-born infants, i.e., “neonates” (0–27 days), infants/toddlers (28 days–2 years), children (2–11 years) and adolescents (11–16 or 18 years).1 As such, age-appropriate formulations are required to maximize efficacy and minimize the risk for dosing errors. Other criteria include ease of preparations and instructions for use for caregivers, acceptability (e.g., palatability and tablet size), the choice and amounts of excipients, as well as use of alternative delivery systems and appropriate packaging.1
However, the intrinsic challenges in developing age-appropriate medicinal products should not be under-estimated. The optimal selection of excipients is a crucial stage in pediatric formulation development; as many excipients that are safe in adults, may be dangerous in children. The Safety and Toxicity of Excipients for Paediatrics (“STEP”) database is an important resource in quickly identifying issues and selecting “age-appropriate” excipients.9
Difficulties in swallowing (i.e., dysphagia) solid-oral dosage forms (i.e., tablets and capsules) can affect many children, particularly the very young.10 This often necessitates the development of “age-appropriate” dosage forms. The development of multi-use oral liquid and parenteral formulations also necessitates the use of preservatives to prevent microbial contamination; as bacterial infections in children can often be dangerous, sometimes fatal. As preservatives are essentially broad-based cytoplasmic toxic ingredients their continuing use in children’s medicines have been extensively debated.11 As most drugs are typically “foul-tasting”, poor taste (or palatability) is one of the most significant formulation challenges. To address this issue, several approaches have been explored including using “sweeteners, flavors, coating, emulsions and liposomes, complexes with cyclodextrins and ion-exchange resins, salts, and polymeric materials”.10 Another significant issue with oral liquid formulations is their intrinsically poor stability (both chemical and physical), as the solution-state is fundamentally less ordered than the solid-state.
Pediatric medicines are vital for the health and well-being of children. However, children are not “small adults”; as in addition to differences in height, weight and age; these groups cover profound developmental, physiological and metabolic changes. As such, adult dosage forms and dosage strengths, whilst being typically applicable for adolescents are often totally inappropriate for premature, neonates, infants and toddlers.10 But developing these “age-appropriate” medicinal products is a challenging and costly undertaking.
1. ICH E11(R!). ICH E11(R1) guideline on clinical investigation of medicinal products in the pediatric population. Step 5. European Medicines Agency. EMA/CPMP/ICH/2711/1999. https://www.ema.europa.eu/en/documents/scientific-guideline/ich-e11r1-guideline-clinical-investigation-medicinal-products-pediatric-population-revision-1_en.pdf. Published September 1, 2017. Accessed August 8, 2021.
2. Paediatric investigation plans. European Medicines Agency. https://www.ema.europa.eu/en/human-regulatory/research-development/paediatric-medicines/paediatric-investigation-plans. Accessed August 8, 2021.
3. Guidance for industry. qualifying for pediatric exclusivity under section 505A of the federal food, drug, and cosmetic act. US Food and Drug Administration. https://www.fda.gov/media/72029/download. Revised September 1999. Accessed August 8, 2021.
4. BPCA Best Pharmaceuticals for Children Act. https://www.nichd.nih.gov/research/supported/bpca. Accessed August 8, 2021.
5. Shawahna R. Pediatric biopharmaceutical classification system: Using age-appropriate initial gastric volume. AAPS J. 2016;18(3):728–736. doi: 10.1208/s12248-016-9885-2
6. Gandhi SV, Rodriguez W, Khan M, Polli JE. Considerations for a pediatric biopharmaceutics classification system (BCS): Application to five drugs. AAPS PharmSciTech. 2014;15(3):601–11. doi: 10.1208/s12249-014-0084-0
7. Martira J, Flanaga T, Mann J, Fotakia N. BCS-based biowaivers: Extension to paediatrics. Eur. J. Pharm. Sci. 2020;155:105549. doi: 10.1016/j.ejps.2020.105549
8. De Cock RFW, Piana C, Krekels EHJ, et al. The role of population PK–PD modelling in paediatric clinical research. Eur. J. Clin. Pharmacol. 2011;67:5–16. doi: 10.1007/s00228-009-0782-9
9. Salunke S, Brandy B, Giacoiac G, Tuleua C. The STEP (Safety and Toxicity of Excipients for Paediatrics) database: Part 2 – The pilot version. Int. J. Pharm. 2013;457(1):310–322. doi: 10.1016/j.ijpharm.2013.09.013
10. Ernest TB, Elder DP, Martini LG, Roberts M, Ford JL. Developing paediatric medicines: identifying the needs and recognizing the challenges. J. Pharm. Pharmac. 2007;59:1043–1055. doi: 10.1211/jpp.59.8.0001
11. Crowley PJ, Elder DP. Preservation of Pharmaceutical Dosage Forms, In Block’s Disinfection, Sterilization and Preservation. 6th Ed. New York, NY; London, UK: Wolters Kluwer; 2020:795–821.