Use of M&S Methods in Pediatric Studies

Clinical trial of pediatric drugs is a highly challenging process despite the numerous regulatory guidelines covering a broad variety of its ethical and practical considerations. The availability of specialized tools for designing and analyzing pediatric studies make it possible to address a range of special requirements in an up-front manner.

One of such tools is the modeling and simulation method (M&S) which allows to retrieve and design a maximum amount of data from information obtained from pediatric trials. Furthermore, the use of M&S techniques has also a clear regulatory basis in pediatric drug development.

Model-based drug development helps answer and support answers to specific questions, given the fact that clinical trials of pediatric drugs are usually conducted with a minimal amount of subjects who are also more vulnerable than adults. In these trials, every attempt should be made to avoid undue risks and to minimize the number of procedures, pain, distress, and fear. M&S helps to achieve reliable results with a smaller amount of available information.

Two perspectives of M&S use in pediatric drug development

  1. M&S tools – such as PBPK modeling, Scaling and Bayesian approaches – can be applied using some prior knowledge, even before any pediatric clinical trial data being available. Allowing to develop designs for pediatric studies and develop dosing recommendations, these simulations can be used for the PIP, to support the pediatric strategy.
  2. Designed to be used with pediatric data during as well as after a clinical trial, M&S tools can analyze sparse population PK analysis and sampling. This reduces the distress among patients and maximizes knowledge generation. 

With the EMA requesting the submission of PIP early in the process of drug development, it is almost always acceptable to provide a general M&S results which can be updated and fine-tuned later as more trial details and results (such as exposure-response relationship in adults) become available.

While there are no guidelines defining the difference between US and EU regulatory assessment of M&S, the acceptance and promotion of the following techniques has been increasing in drug development in general and in pediatrics in particular:

  • Physiologically based PK (PBPK) modeling
  • Optimal design
  • Population PK and PK/PD modeling

Physiologically based PK (PBPK) modeling

Being based on physiological considerations, PBPK models deliver more comprehensive results than semi-mechanistic or empirical models. PBPK models facilitate predictions of drug exposure in different age groups. They also allow to predict sampling times and to optimize the dosing schedule.

With drug-specific and physiological parameters being included in the model, in vitro predictions are utilized for elimination and distribution. Compartments in the PBPK model represent real tissue and organ construction with realistic physical volumes of tissues and organs. Mass balance equations describe the elimination of the drug into the different organs and its appearance from arterial blood.

Validation of a PBPK model with pharmacokinetics data makes it possible to reveal differences in maturation and growth, and thus make predictions about drug exposure in children.

The support of PBPK modeling for finding pediatric dose in infants and neonates is substantial (with the dose scaling approaches being applicable to children above two years of age, too). The already established physiological models for children incorporate the available knowledge and allow to make accurate predictions about how the age may affect certain aspects of PK and PD.

After PBPK performance being proven, there are a few PBPK software systems commercially available to be used in describing and predicting pharmacokinetics in children.

Design optimization

The limited number of patients and samples in clinical studies lead to the need of optimizing the study design and making sampling more informative. The following optimization and evaluation strategies help to achieve this goal.

  • Use of prior information – such as PK in adult patients including covariates – in evaluating a sparse sampling.
  • Use of D-optimality sampling method for finding smallest errors in the parameter estimation.
  • Use of the suggested sampling times developed through D-optimality.  It makes possible to simulate a large number of trials and employ population PK methods to estimate the obtained parameters. The obtained estimates can be further compared to the (“true”) parameters which were used for the given simulation.

Population PK and PD/PD modeling

It is possible to develop population PK and PD/PD models basing not only on data from previous clinical trials but also data pooled from different studies.

Explicitly recommended in various regulatory guidelines, population PK and PD/PD modeling is indispensable in pediatric drug study as a primary analysis method, which is applicable to unbalanced and sparse data sets in children, neonates, etc. They can form a reliable scientific basis for labeling extensions in other populations, for dose adjustment and trial/study simulations. Furthermore, it is possible to extrapolate from older children and adults, as well as extrapolate efficacy (if applicable) employing PK parameters. Included in drug label should be the dosing regimens developed through population PK and PD/PD models, provided that the model is validated and its predictive value is sufficiently presented.

This modeling technique can be used to bridge the gap between children and adults when being combined with other data like disease characteristics and exposure-response relationship obtained from adults.

Overall, M&S techniques have become a well-established component of drug development. Recommended by major regulatory documents, they prove to be effective in such areas of pediatric drug development as study design and dose finding, bringing to minimum pediatric population’s pain, distress, and fear.

What is more, one of the FDA 2020 vision components contains a regulation to include simulations into all pediatric clinical trials, making it an integral part of them. Therefore, drug developers should pursue further the employment of M&S techniques in order to comply with the regulatory requirements in pediatric drug development, and make their contribution into development of new standards and techniques in that area, as well as improve performance in the pediatric drugs’ industry in general.