Pediatric Drug Development: Key Considerations and Challenges

Pediatric medicines, often referred to as “age-appropriate” or “child-friendly,” are vital to the health and well-being of children. Nevertheless, a core principle in any pediatric drug development program is that “children should not be enrolled in a clinical trial unless necessary to fulfill an important pediatric public health need”.1 As such, the balance between risks and likely clinical benefits must be assessed. . and the child must not be adversely affected by participating in the study.

Regulators have tried to encourage, mandate and support the development of ‘child-friendly’ medicines. The International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) recently updated ICH-E11(R1) outlining “an approach to the safe, efficient and ethical study of drugs in the pediatric population.”1 In Europe’s development of pediatric medicines is aimed at preventing children from undergoing unnecessary clinical examinations; facilitating research on pediatric drugs and pediatric dosage forms; and improving the labeling of pediatric drugs. The European Medicines Agency (EMA) has introduced a Pediatric Investigation Plan (PIP), which is a requirement for all new pediatric products.2 The U.S. Food and Drug Administration (FDA) pediatric exclusivity initiative provides for an additional six-month or additional exclusivity patent protection in exchange for initiating pediatric clinical trials.3 Subsequently, the Best Pharmaceuticals for Children Act (BPCA) established a procedure for the study of pediatric uses of generics, to study pediatric uses of non-generics where no pediatric drugs are available. were available and approved the publication of all new findings

In certain cases, it is recognized that there will be intrinsic difficulties in generating data on a pediatric population due to a variety of ethical considerations and feasibility issues.1 Alternative approaches may provide opportunities to address these issues. These include modeling of biopharmaceutical classification systems, 5,6,7 pharmacokinetic-pharmacodynamic modelling,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 heterogeneous group, spanning the first two decades of life and divided into five subclasses of patients. Premature, newborn infants, ie “premature”, term newborn infants, ie “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 of dosing errors. Other criteria include ease of preparation and instructions for use for healthcare providers, acceptability (e.g., palatability and tablet size), choice and amounts of excipients, as well as the use of alternative delivery systems and appropriate packaging.1

However, the intrinsic challenges in developing age-appropriate drugs should not be underestimated. The optimal selection of excipients is a critical stage in the development of pediatric formulations; so many excipients that are safe in adults can be dangerous in children. The Safety and Toxicity of Excipients for Pediatrics (“STEP”) database is an important tool for quickly identifying problems and selecting “age-appropriate” excipients.9

Difficulty swallowing (ie dysphagia) solid oral dosage forms (ie tablets and capsules) can affect many children, especially the very young.10 This often requires the development of “age-adjusted” dosage forms. The development of multi-use oral liquid and parenteral formulations also requires the use of preservatives to prevent microbial contamination; as bacterial infections in children can often be dangerous and sometimes fatal. Since preservatives are essentially broad-based cytoplasmic toxic ingredients, their continued use in pediatric drugs has been widely discussed.11 Since most drugs are typically “tasteless,” one of the major formulation challenges is poor taste (or palatability). . To address this issue, several approaches have been explored, including the use of “sweeteners, flavors, coatings, emulsions and liposomes, complexes with cyclodextrins and ion exchange resins, salts and polymeric materials”.10 Another major problem with oral liquid formulations is their intrinsically poor stability (both chemical and physical), since the solution state is fundamentally less ordered than the solid state.

Medicines for children are vital to the health and well-being of children. However, children are not “little adults”; as in addition to differences in height, weight and age; these groups include profound developmental, physiological, and metabolic changes. As such, dosage forms and dosage strengths for adults, while typically applicable to adolescents, are often totally unsuitable for premature infants, neonates, infants and toddlers.10 But developing these “age-adjusted” drugs is a challenging and costly undertaking.


1. ICH E11(R!). ICH E11(R1) guideline for clinical trial of medicinal products in the pediatric population. Step 5. European Medicines Agency. EMA/CPMP/ICH/2711/1999. Published September 1, 2017. Accessed August 8, 2021.

2. Pediatric Investigation Plans. European Medicines Agency. Accessed on August 8, 2021.

3. Industry Guidance. eligible for pediatric exclusivity under Section 505A of the Federal Food, Drug, and Cosmetic Act. US Food and Drug Administration. Revised September 1999. Accessed August 8, 2021.

4. BPCA Best Pharmaceuticals for Children Act. Accessed on August 8, 2021.

5. Shawahna R. Pediatric Biopharmaceutical Classification System: Use of 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 Biopharmaceuticals (BCS) Classification System: 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 pediatrics. EUR. J. Farm. Science. 2020;155:105549. doi: 10.116/j.ejps.2020.105549

8. De Cock RFW, Piana C, Krekels EHJ, et al. The role of population PK-PD modeling in pediatric 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 Pediatrics) Database: Part 2 – The Trial Version. int. J. Farm. 2013;457(1):310-322. doi: 10.116/j.ijpharm.2013.09.013

10. Ernest TB, Elder DP, Martini LG, Roberts M, Ford JL. Pediatric drug development: identifying needs and recognizing the challenges. J. Farm. Pharmacy 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 edition. New York, NY; London, UK: Wolters Kluwer; 2020: 795-821.

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