Practical and operational considerations related to paediatric oral drug formulation: An industry survey

https://doi.org/10.1016/j.ijpharm.2022.121670Get rights and content

Abstract

For over 15 years, US and EU regulations ensure that medicines developed for children are explicitly authorised for such use with age-appropriate forms and formulations, implying dedicated research. To shed light on how these regulations have been adopted by pharmaceutical companies and how various aspects of paediatric oral drug formulation development are currently handled, an exploratory survey was conducted. Topics included: general company policy, regulatory aspects, dosage form selection, in-vitro, in-silico and (non-)clinical in-vivo methods, and food effects assessment. The survey results clearly underline the positive impact of the paediatric regulations and their overall uptake across the pharmaceutical industry. Even though significant improvements have been made in paediatric product development, major challenges remain. In this respect, dosage form selection faces a discrepancy between the youngest age groups (liquid products preference) and older subpopulations (adult formulation preference). Additionally, concerted research is needed in the development and validation of in-vitro tools and physiology based pharmacokinetic models tailored to the paediatric population, and in estimating the effect of non-standard and paediatric relevant foods. The current momentum in paediatric drug development and research should allow for an evolution in standardised methodology and guidance to develop paediatric formulations, which would benefit pharmaceutical industry and regulators.

Introduction

Paediatric drug research has long been predominantly governed by the extrapolation of knowledge gained in adults without actually testing medicines in children. The understanding of age-dependent physiological changes and their impact on drug disposition has long been obscure and systematic research activities only emerged in recent years (Hirschfeld and Saint-Raymond, 2011, Richey et al., 2013; Miller and Letendre, 1999; Turner et al., 2014; Shirkey, 1968). The vulnerability of the paediatric population within clinical research, practical difficulties in recruiting paediatric patients, decreased commercial interest, increased cost, and a greater risk of liability, remained pivotal arguments to neglect paediatric centred research and drug development. Moreover, until recently, the small market share and comparatively smaller return on investment often caused paediatric drug development programmes to be driven by a company’s product development strategy for the adult population, rather than the actual paediatric needs (Bourgeois et al., 2012, Joseph et al., 2015, Saint Raymond and Brasseur, 2005, Turner, 2015).

It took decades of concerted efforts by regulatory agencies to shift paediatric medicines development from “therapeutic or pharmaceutical orphans” to the centre stage of drug development research. This shift was driven by the Best Pharmaceuticals for Paediatrics Act (BPCA) (U.S. Governement, 2002) and the Pediatric Research Equity Act (PREA) (U.S. Governement, 2003) by the Food and Drug Administration (FDA), and the Regulation No 1901/2006 on medicinal products for paediatric use (The European Parliament and the Council of 12 December 2006, 2006) by the European Medicines Agency (EMA). The current US and EU regulations ensure that the medicines developed for children are explicitly authorised for such use with age-appropriate forms and formulations. As these regulations have now been implemented for over 15 years, it is interesting to investigate how these regulations were adopted and implemented by pharmaceutical companies into drug development. The approach to paediatric product development is still evolving and the toolbox for prediction of performance of medicines in paediatric populations is fragmented. The current publication reports the results of an industry survey that gauges how paediatric drug formulation and specifically prediction of in-vivo performance is currently being handled within the pharmaceutical industry. As oral formulations are mostly used for the paediatric population, the focus was on oral product development. Questioned topics include: general information regarding the company policy, regulatory strategies, dosage form selection criteria, in-vitro, in-silico and non-clinical in-vivo methods in the development of paediatric formulations and food effects assessment.

Section snippets

Materials and methods

An exploratory survey was designed with the aim to get insight into how paediatric drug development is handled in the pharmaceutical industry. The topics included in the survey were not limited to activities within the framework of the regulatory requirements but also focussed on an R&D perspective. Participants were asked to consider all activities related to paediatric drug development, including successful and failed drug development projects, as well as non-commercial research-based

Participant demographics

In total, 12 companies provided a response to the questionnaire. Of the 12 responding companies, 2 acted as individual respondents while the other 10 companies responded as a team. As shown in Fig. 1, the respondents covered a wide spectrum of expertise within the pharmaceutical industry, with formulation development and biopharmaceutics being the most represented, followed by clinical research and regulatory.

Discussion

This survey gives some insight in how paediatric biopharmaceutics are handled in the pharmaceutical industry. Insight was provided by experienced scientists in 12 pharmaceutical companies which are actively performing paediatric research and development and have paediatric drugs on the market. Questioned topics included general information regarding company policies, regulatory hurdles, selection of the appropriate dosage form, in-vitro, in-silico and non-clinical in-vivo techniques, and food

Conclusion

As a summary, the survey results clearly underline the positive impact of the paediatric regulations and their overall uptake across the pharma industries. Even though significant improvements have been made, major challenges still remain in the implementation of paediatric physiology into in-vitro setups, more tailored and validated PBPK models, the effect of non-standard and paediatric relevant foods and age appropriate and flexible paediatric dosage forms. However, with the current momentum

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Shriram M. Pathak is an employee of Quotient Sciences, Nottingham, United Kingdom.

Acknowledgements

This work was supported by Research Foundation Flanders (FWO, research grant G0A8119N). The authors would like to thank the members of the community leadership of the Oral Biopharmaceutics and Absorption Modelling community of AAPS for the fruitful discussions which (1) have resulted in the Paediatric Biopharmaceutics webinar series (available on the AAPS website) and (2) triggered the organisation of the present questionnaire. We also thank those who took the time to complete and return this

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