Justin Hay, Senior Director, Amy Cheung Senior Director of Integrated Drug Development, and Patrick Loebs Director, at Certara, examine recent changes in paediatric guidelines and how they affect drug development projects.
It has been a very busy period recently for paediatric drug development with the release of many guidance documents from two notable regulatory agencies. The United States Food and Drug Administration (FDA) has released four draft paediatric guidelines for comment:
- Ethical Considerations for Clinical Investigations of Medical Products Involving Children (July 2022)
- General Clinical Pharmacology Considerations for Paediatric Studies of Drugs, Including Biological Products (September 2022)
- Measuring Growth and Evaluating Pubertal Development in Paediatric Clinical Trials (October 2022)
- Considerations for Long Term Clinical Neurodevelopment Safety Studies in Neonatal Product Development (February 2023)
Likewise, the European Medicines Agency (EMA) has recently released (February 2023) the Guidance for Stepwise Paediatric Investigation Plan (sPIP) pilot as part of the closing report of the EMA and European Commission (EC) action plan on paediatrics.
The pharmaceutical industry is constantly developing evidence-based treatments for children while there continue to be scientific advancements related to new modalities and disease understanding. As such, guidance from the FDA and EMA on paediatric drug development and long-term safety is greatly appreciated, particularly given the unique challenges presented by this vulnerable population. These guidelines facilitate open communication between regulators and researchers, enabling the industry to adapt and conduct more robust and efficient paediatric clinical studies, while avoiding unnecessary trials. This article will summarise these five guidelines, with a specific focus on modelling and simulation when it is discussed.
Given the vulnerable status of children, safeguards are needed when including a paediatric population in clinical investigations of drugs and medical devices. In addition to describing the ethical framework (eg. including a description of risk categories based on benefit) for conducting paediatric investigations, this FDA guideline considers situations where, if the effectiveness in adults can be extrapolated to children, then collecting effectiveness data in children can be minimised. From a modelling and simulation perspective, the guideline suggests that modelling may provide evidence of prospect of direct benefit which is important with regards to 21 CFR 50.52. Furthermore, the guideline discusses the data requirements to support paediatric clinical investigations for both drugs and devices as well as the procedures needed for sedation in paediatric clinical investigations.
General clinical pharmacology
This FDA draft guidance was previously issued in 2014 but was re-issued for comments again in 2022. The guidance covers three main areas: clinical pharmacology considerations, ethical considerations, and the paediatric study plan design including points to consider. The section on ‘clinical pharmacology considerations’ covers the physiological differences in paediatric patients that can be attributed to pharmacokinetics and pharmacodynamics of the compound/drug of interest. Ethical considerations are critical to clinical pharmacology studies as these studies generally don’t provide a direct clinical benefit to the patient and the vulnerable population involved. The section on ethics covers two examples of paediatric ethical factors to consider. One discusses studies which involve ‘no more than a minor increase over minimal risk.’ The other considers studies that ‘offer the prospect of direct benefit to the participant.’ The final section provides practical and pragmatic approaches to clinical study design in paediatric patients including important considerations regarding dose formulation and selection, sample size, sample collection and analysis, relative bioavailability, food interactions and drug-drug interactions (DDIs), amongst others.
Physiologically based pharmacokinetic (PBPK) modelling (mechanistic models that incorporate tissue volume and blood flow rate parameters and metabolite/enzyme kinetic information to help define the PK of a drug) and simulation are growing in importance for drug development, especially for paediatric populations where ontogeny was incorporated into the PBPK model. The guidance mentions PBPK four times regarding renal function and DDIs. Also, PBPK would be beneficial for integrating all drug-dependent parameters into an in-silico model that can be used to optimise the study design.
One section of the guidance discusses alternative approaches to conventional PK studies which rely on intensive PK sampling – especially as taking blood or tissue samples is challenging when designing and conducting paediatric trials. Modelling and simulation have long complemented studies that utilise sparse and opportunistic PK sampling as well as the incorporation of parameters derived from alternative specimens into the model such as urine, saliva, tissue, and cerebrospinal fluid (CSF). The guideline also explains how model-informed drug development (MIDD) can be utilised, such as for planning first-in-paediatric PK studies, optimising the study design, and recommending starting doses.
Beyond the guidance, there are situations where the indication, or a labelled dose proposal could be based on modelling (PBPK and/or population PK), especially when including paediatric patients is particularly challenging and/or minimal observed data are available. This approach, together with very sparse, confirmatory PK data, for example, is discussed by Small et al. 2022.1
Paediatric PBPK models are being used increasingly to leverage existing knowledge to allow a more mechanistic approach to inform dose selection for both small and large molecules and formulation bridging, extrapolate DDIs, and identify knowledge gaps such as discussed in Johnson et al. 2022.2
Growth and pubertal development
Accurate and reliable serial measurements of growth and pubertal development are important for evaluating safety of paediatric populations in clinical studies including clinical pharmacology studies. The FDA guideline provides guidance on various aspects including height (length in children from birth to less than two years of age), weight, head circumference, as well as age. There is a lack of consensus when calculating age for children less than three months of age, but the guidance provides direction. This guidance also provides valuable insights into the agency’s thoughts on what types of measurements and validated assessments should be considered when assessing pubertal development and skeletal age.
Long term clinical neurodevelopment safety studies
The FDA has issued guidance for developing long-term clinical neuro-developmental safety studies for products intended for neonates. The neonatal period is a critical time of growth and physiological development for all organs and systems but particularly the respiratory and cardiovascular systems. For the Central Nervous System (CNS), the neonate brain lacks cerebral auto-regulation, and the blood brain barrier is immature and weak thus medications permeate the CNS more easily3. Neonates also have an increased amount of CSF and immature myelination3. Short-term safety evaluations may fail to identify possible accumulative or late-onset adverse effects that are only apparent upon long-term observation. Therefore, this guidance provides a framework for considering neuro-developmental evaluations. The likelihood of needing to evaluate neuro-developmental safety increases with CNS and systemic exposure, the timing and duration of exposure, the characteristics of the population, and the pharmacology of the product being investigated. The guidance outlines the study design and data collection considerations for evaluating the potential adverse effects on neurodevelopment, including cognitive, behavioural, and functional outcomes. The guidance stresses the importance of designing studies with appropriate control groups, follow-up periods, and statistical power, as well as considering the potential impact of confounding factors. The goal of these studies is to inform the safety of neonatal product development and improve outcomes for this vulnerable population.
Stepwise paediatric investigation plans (sPIPs)
Recently the closing report of the EMA and EC action plan on paediatrics was published, a culmination of four years of work. One of the action points was the launch of the pilot phase for a sPIP. The guidance is for pharmaceutical companies conducting paediatric clinical trials in the EU using the PIP procedure. PIPs are mandatory for applicants seeking marketing authorisation for new medicines in the EU. They are required for orphan drugs but not for biosimilars. This guidance outlines a pilot program for sPIPs to encourage early dialogue and optimise the design of paediatric clinical trials. The guidance provides detailed information on the pilot program, including eligibility criteria, timelines, and the submission process, as well as recommendations for best practices in PIP development and implementation.
The voluntary pilot scheme will start with eight sPIPs and will target medicines where elements of the PIP cannot be defined. These include developing a first medicine for a newly identified disease in children, a medicine with an unknown mechanism of action that may affect changes in paediatric development (ontogeny), or a medicine with multiple potential uses to address significant unmet needs in various paediatric indications where adult data are lacking. Overall, the guidance aims to promote developing safe and effective medicines for children in the EU through a streamlined and collaborative regulatory process. While the guideline does not address modelling and simulation per se, it recognises that MIDD plays a crucial role in paediatric drug development and PIP and Paediatric Study Plans.
So far, the first three of these guidelines have received high-quality comments from external parties and industry members who anticipate seeing these helpful guidance documents being finalised in the not-so-distant future. The announcement by the EMA of the pilot guidance for sPIPs is greatly welcomed. This is exciting for the paediatric regulatory community and industry as it acknowledges that developing medicines is a “dynamic process dependent on the result of ongoing studies.” It also means that development and testing of medicines for use in children is adapting to a more flexible, ethical, and scientifically valid process and will no doubt lead to children receiving more safe and effective treatments in the future.
About the authors
Dr. Justin Hay is a Senior Director at Certara with more than 20 years of clinical pharmacology experience. Career highlights include working as Senior Pharmacokinetics Assessor and Deputy Unit Manager at the Medicines and Healthcare products Regulatory Agency (MHRA) in the United Kingdom. He has also been a member of the EMA’s Modelling and Simulation Working Party.
Dr. Amy Cheung has more than a decade of experience working in the pharmaceutical industry at AstraZeneca, with her role as Senior Pharmacometrician and Project Manager of AZ Paediatric working group. She obtained her PhD from the University of Manchester on the topic of Structural Identifiability Analysis in Pharmacokinetic and Pharmacodynamic Models.
Patrick Loebs is a Director at Certara with 35-plus years of industry experience in the clinical research organisation, pharmaceutical, academic and biotech space. He has held positions in regulatory affairs, regulatory operations, medical writing, clinical operations, and program management. Most recently, while Regulatory Program Manager, he assisted in the development of two transgenic recombinant products that treat blood disorders.
- Small BG, Johnson TN, Rowland Yeo K. Another Step Toward Qualification of Pediatric Physiologically Based Pharmacokinetic Models to Facilitate Inclusivity and Diversity in Pediatric Clinical Studies [published online ahead of print, 2022 Oct 28]. Clin Pharmacol Ther. 2022;10.1002/cpt.2777. doi:10.1002/cpt.2777
- Johnson TN, Small BG, Rowland Yeo K. Increasing application of pediatric physiologically based pharmacokinetic models across academic and industry organizations. CPT Pharmacometrics Syst Pharmacol. 2022;11(3):373-383. doi:10.1002/psp4.12764
- Doherty TM, Hu A, Salik I. Physiology, Neonatal. [Updated 2022 Apr 28]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK539840/