Pediatric drug development: key considerations and challenges
Pediatric drugs, often called “Age-appropriate” or “child-friendly”, are essential to the health and well-being of children. Nonetheless, a fundamental principle of any pediatric drug development program is that “children should not be included in a clinical study unless it is necessary to meet a significant pediatric public health need”.1 As such, the balance of risk and likely clinical benefit should be weighed and the child should not be adversely affected by enrollment in the research study.
Regulators have attempted to encourage, mandate and support the advancement of “child-friendly” drugs. The International Council for the Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) recently updated ICH-E11 (R1), which describes “an approach for a safe, effective and ethical study of drugs in the pediatric population ”.1 In Europe, the development of pediatric medicines aims to prevent children from undergoing unnecessary clinical investigations; facilitate research on pediatric drugs and pediatric dosage forms; and improving the labeling of pediatric drugs. The European Medicines Agency (EMA) has a Pediatric Investigation Plan (PIP) in place, which is a prerequisite for all new pediatric products.2 The U.S. Food and Drug Administration (FDA) pediatric exclusivity initiative provides an additional six-month exclusivity or additional patent protection in exchange 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 when no pediatric drug was available. and approved the publication of all new findings.4
In some cases, it is recognized that there will be inherent difficulties in generating data on a pediatric population due to a variety of ethical considerations and feasibility issues.1 Alternative approaches can provide opportunities to address these concerns. These include the modeling of the biopharmaceutical classification system,5,6,7 pharmacokinetic-pharmacodynamic modeling,8 etc. Modeling can also be used for “clinical trial simulation, dose selection, study design choice and optimization, endpoint selection and pediatric extrapolation”.1
“Children” are a very large and heterogeneous group, spanning the first two decades of life and subdivided into five subclasses of patients. Premature neonates, ie “premature”, term neonates ie “newborns” (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 needed to maximize efficacy and minimize the risk of dosing errors. Other criteria include ease of preparation and instructions for use by caregivers, acceptability (for example, palatability and tablet size), choice and amounts of excipients, and use. alternative distribution systems and appropriate packaging.1
However, the inherent challenges of developing age-appropriate medicines should not be underestimated. Optimal selection of excipients is a crucial step in the development of a pediatric formulation; like many excipients that are safe for adults, may be harmful to children. The Safety and toxicity of excipients for pediatrics (“STEP”) is an important resource for quickly identifying problems and selecting “age appropriate” excipients.9
Difficulty in swallowing (i.e. dysphagia) oral solid dosage forms (i.e. tablets and capsules) can affect many children, especially very young.ten This often requires the development of “age appropriate” dosage forms. The development of oral and parenteral formulations for multiple uses also requires the use of preservatives to avoid microbial contamination; because bacterial infections in children can often be dangerous, sometimes fatal. As preservatives are primarily broad based cytoplasmic toxic ingredients, their continued use in pediatric medicines has been widely debated.11 Since most drugs generally have a “bad taste,” bad taste (or palatability) is one of the most important formulation challenges. To solve this problem, several approaches have been explored, including the use of “sweeteners, flavors, coatings, emulsions and liposomes, complexes with cyclodextrins and ion exchange resins, salts. and polymer materials ”.ten Another significant problem with oral liquid formulations is their inherently low stability (both chemical and physical), since the solution state is inherently less ordered than the solid state.
Pediatric medicines are vital for the health and well-being of children. However, children are not “little adults”; in addition to the differences in height, weight and age; these groups cover profound developmental, physiological and metabolic changes. As such, dosage forms and strengths for adults, while generally applicable to adolescents, are often completely unsuitable for premature infants, newborns, infants and toddlers.ten But developing these “age-appropriate” drugs is difficult and expensive.
1. ICH E11 (R!). ICH E11 (R1) guideline on the 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. Posted September 1, 2017. Accessed August 8, 2021.
2. Pediatric 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. Orientation for industry. eligible for pediatric exclusivity under Section 505A of the Federal Food, Drug and Cosmetic Act. United States Food and Drug Administration. https://www.fda.gov/media/72029/download. Revised September 1999. Accessed August 8, 2021.
4. Best Pharmaceuticals for Children Act BPCA. 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. do I: 10.1208 / s12248-016-9885-2
6. Gandhi SV, Rodriguez W, Khan M, Polli JE. Considerations for a pediatric biopharmaceutical classification system (BCS): application to five drugs. AAPS PharmSciTech. 2014; 15 (3): 601–11. do I: 10.1208 / s12249-014-0084-0
7. Martira J, Flanaga T, Mann J, Fotakia N. BCS-based biowaivers: extension to pediatrics. EUR. J. Pharm. Sci. 2020; 155: 105549. do I: 10.1016 / 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. do I: 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. do I: 10.1016 / j.ijpharm.2013.09.013
ten. Ernest TB, Elder DP, Martini LG, Roberts M, Ford JL. Develop pediatric drugs: identify the needs and recognize the issues. J. Pharm. Pharmac. 2007; 59: 1043-1055. do I: 10.1211 / jpp.59.8.0001
11. Crowley PJ, former DP. Storage of pharmaceutical dosage forms, in Block’s Disinfection, Sterilization and Storage. 6th ed. New York, NY; London, UK: Wolters Kluwer; 2020: 795-821.