Practical and operational considerations related to paediatric oral drug formulation: An industry survey
Graphical abstract
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
References (57)
- et al.
A toolbox for mimicking gastrointestinal conditions in children: simulated paediatric breakfast media (SPBM) for addressing the variability of gastric contents after typical paediatric breakfasts
J. Pharm. Sci.
(2022) - et al.
In vitro gastrointestinal model (TIM) with predictive power, even for infants and children?
Int. J. Pharm.
(2013) - et al.
Best practices in the development and validation of physiologically based biopharmaceutics modeling. A workshop summary report
J. Pharm. Sci.
(2021) - et al.
Development of medicines for children in Europe: ethical implications
Paediatr. Respir. Rev.
(2005) - et al.
The influence of gastric emptying kinetics on the drug release from enteric coated pellets in fasted state: an in vitro/in vivo correlation
Eur. J. Pharm. Biopharm.
(2012) - et al.
Impact of gastrointestinal physiology on drug absorption in special populations––an UNGAP review
Eur. J. Pharm. Sci.
(2020) Editorial comment: Therapeutic orphans
J. Pediatr.
(1968)Pediatric oral formulations: an updated review of commercially available pediatric oral formulations since 2007
J. Pharm. Sci.
(2019)- et al.
Paediatric drug development: the impact of evolving regulations
Adv. Drug Deliv. Rev.
(2014) - et al.
Gastric fluid composition in a paediatric population: Age-dependent changes relevant for gastrointestinal drug disposition
Eur. J. Pharm. Sci.
(2018)
Current challenges and future perspectives in oral absorption research: An opinion of the UNGAP network
Adv. Drug Deliv. Rev.
Paediatric nurses’ knowledge and practice of mixing medication into foodstuff
Int. J. Pharm. Pract.
Influence of food on paediatric gastrointestinal drug absorption following oral administration: a review
Children
Formulations for children: problems and solutions
Br. J. Clin. Pharmacol.
Does age affect gastric emptying time? A model-based meta-analysis of data from premature neonates through to adults
Biopharm. Drug Dispos.
Pediatric versus adult drug trials for conditions with high pediatric disease burden
Pediatrics
Measurement of gastrointestinal pH profiles in normal ambulant human subjects
Gut
Measurement of gastrointestinal pH and regional transit times in normal children
J. Pediatr. Gastroenterol. Nutr.
Quantification of fluid volume and distribution in the paediatric colon via magnetic resonance imaging
Pharmaceutics
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