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Clinical investigation of medicinal products in the pediatric population – Addendum to ICH E11

  • 17 October 2017
  • clinical trial, drug development, extrapolation, formulation, ICH E11, modeling, pediatric formulation, pediatric population, simulation,

ASE Pharma Solutions

On 6 October 2017, the European Medicines Agency (EMA) published revised version of ICH E11(R1) guideline on clinical investigation of medicinal products in the pediatric population in the form of an addendum. This document will become effective on 28 February 2018.

Pediatric drug development has evolved since the original ICH E11 Guideline (2000), requiring consideration of regulatory and scientific advances relevant to pediatric populations. The addendum does not alter the scope of the original guideline which outlines an approach to the safe, efficient, and ethical study of medicinal products in the pediatric population but complement and provide clarification and current regulatory perspective on topics in pediatric drug development. Additionally, this harmonized addendum will help to define the current recommendations and reduce the likelihood that substantial differences will exist among regions for the acceptance of data generated in pediatric global drug development programs and ensure timely access to medicines for children.

informed consent


ICH E11(R1) supplements ICH E11 in several areas, reflecting various progress in pediatric drug development, especially in extrapolation, modeling and simulation (M&S), trial methodology, and formulation.

It is important to notice that during clinical studies there is a requirement for obtaining adequate informed consent for continued participation from pediatric participants once a child reaches the age of legal consent (ethical issue).


“Pediatric extrapolation” is defined as an approach to providing evidence in support of effective and safe use of drugs in the pediatric population when it can be assumed that the course of the disease and the expected response to a medicinal product would be sufficiently similar in the pediatric and reference (adult or other pediatric) population.

The process of pediatric extrapolation examines several factors that support the assumptions of similarity of disease and similarity of response to therapy, including evidence to support exposure-response relationship, between the pediatric and the reference populations (e.g., disease pathogenesis, criteria for disease diagnosis).

It is important to be aware about uncertainties and/or limitations of existing data (e.g., clinical or historical data and published literature) and remaining uncertainties about the pediatric population. In the latter case, additional information should be generated (e.g., information from M&S, animal, adult, pediatric subgroup studies) in order to inform the acceptability of the extrapolation approach.


Advancement in clinical pharmacology and quantitative M&S techniques has enabled progress in utilizing model-informed approaches (e.g., mathematical/statistical models and simulations based on physiology, pathology and pharmacology) in drug development. M&S can help quantify available information and assist in defining the design of pediatric clinical studies and/or the dosing strategy. Considering the limited ability to collect data in the pediatric population, pediatric drug development requires tools to address knowledge gaps. M&S is one such tool that can help avoid unnecessary pediatric studies and help ensure appropriate data are generated from the smallest number of pediatric patients.

Scientist and modelling

The usefulness of M&S in pediatric drug development includes, but is not limited to,

  • clinical trial simulation,
  • dose selection,
  • choice and optimization of study design,
  • endpoint selection
  • and pediatric extrapolation.

With M&S, quantitative mathematical models are built with all available and relevant sources of existing knowledge. Well conducted M&S can inform on the pharmacokinetics,

pharmacodynamics, efficacy and safety of a drug. Emerging knowledge is incorporated into the model in an iterative approach to revisit and improve the model.

In pediatrics, it is particularly critical to consider the maturation of organ systems with the understanding that data from older subgroups may not necessarily be informative for the younger subgroups.

Risk assessment is a critical part of M&S. The clinical and statistical consequences of a specific approach should be discussed with experts to define the risks to be handled. The risks associated with accepting the model depend on the relative contribution of the model in making a decision during product development and its consequences. These risks should be assessed and weighed against the credibility of the model for the context of use.


Doctor and child


There are three key practical factors to consider:

  • feasibility (a small number of eligible children for clinical research; limited pediatric specific resources at research centers; the scarcity of dedicated pediatric trial networks),
  • outcome assessments (appropriate endpoints for specific age and developmental subgroups; the evaluation of potential pediatric endpoints as part of the adult development program),

  • and long-term clinical aspects, including safety (pediatric-specific adverse events are unlikely to be detected in development programs that are limited in size and duration; planned collection of safety data in nonclinical studies, adult clinical studies regardless of dose or indication, or information from other sources (e.g., M&S); planned collection of long-term effects of drug treatment in children including impacts on development, growth, and/or maturation of organ/system function with, adequate baseline data assessments).


For purposes of the ICH E11(R1) guideline, the term “pediatric formulations” includes design considerations for the dosage form, route of administration, packaging, measuring or administration device of a pediatric medicine (drug).

Adult dosage forms are not always appropriate for use in the pediatric population, and if a product for adults is used, it may pose a safety risk (e.g., multiple small volume acquisitions from a vial designed for a single adult use; breaking tablets for dose reductions that do not have a functional score line). Therefore, planning for development of age-appropriate dosage forms for pediatric populations should be incorporated into the earliest stages of drug development.


measurement device


There are some important considerations for pediatric formulations to optimize efficacy and reduce the risk for medication and dosing errors including:

  • age-appropriate dosage forms (more than one dosage form of the active pharmaceutical ingredient (API) and/or strengths may be needed to cover the range of pediatric populations intended to receive the medicinal product; formulation development for neonates requires special attention in terms of its physiological effects, method of delivery and environmental conditions such as temperature, light);
  • ease of preparations and instructions for use for caregivers (long acting formulations may be beneficial in settings where the caregiver is not always available (e.g., school); the ease of accurate dose measurement and the capability to deliver small volumes of liquids, especially in neonates, infants and young children);
  • acceptability (e.g., palatability – ideally, the preparation should have a neutral taste or a taste with broad cultural acceptance; tablet size – infants are unable to swallow conventionally-sized tablets; alternative dose administration strategies should be considered as crushing tablets, co-administration with food or liquids);
  • choice and amount of excipients (excipients may lead to adverse reactions in children that are not observed (or not to the same extent) in adults; alternatives to excipients that pose a significant risk to children should always be considered, and the risk posed by the excipient weighed against the severity of the disease and availability of alternative treatments)
  • as well as use of alternative delivery systems and appropriate packaging.