![]() ![]() The common ground in current guidelines is that there are pointers to the lack of safety data on excipients and that available data generally does not apply to neonates requiring further justification including provision of non-clinical safety data. This is insufficient considering the much wider and complex needs of neonates and lack of clarity about how this limited guidance is to be translated into patient-centric product development, which meets with regulatory approval. The capability to administer small volumes in relation to dosing error is also mentioned. In these guidelines, a rather general and brief set of considerations are made in terms of formulation and around polypharmacy via parenteral routes of administration in the hospital setting. In terms of international guidance, it is only in the latest revision of the ICH E11 Guideline on Clinical Investigation of Medicinal Products in the Paediatric Population (2018) that neonates are specifically mentioned as an age classification and paediatric subgroup. The situation is not helped by a relative lack of relevant guidelines on the development of medicines for neonates (let alone those born prematurely). An international consortium of experts has produced a white paper to facilitate successful neonatal clinical trials of medicines and includes useful information on neonatal dosage forms and formulations. There is a ‘Catch 22′ situation because to protect neonates, trials have been deferred so that safety and efficacy data are obtained in older age groups meanwhile the unmet needs gap widens, necessitating off-label use. In fact, trials open for recruiting neonates were included in only a quarter of all agreed paediatric investigation plans (PIPs), often at the request of the EMA Paediatric Committee (PDCO), due to an array of reasons: Lack of neonate specific indications, recruitment/enrollment challenges, lack of incentives. Considering the extra challenges they present, pharmaceutical companies are not incentivised to formulate medicines for the neonatal population. This remains an even more significant problem in the neonatal population, due to the difficulty in conducting the necessary clinical trials in vulnerable subsets with lower patient numbers. In paediatric patients, there is still significant off-label use of medicines due to a lack of medicines developed and authorised for the specific needs of the very young. The recent European Medicines Agency (EMA) report to the European Commission on the experience acquired as a result of the first 10 years application of the Paediatric Regulation, acknowledged that neonates still represent a particularly neglected paediatric subpopulation in the development of medicines despite the regulatory push. This includes (amongst others) formulation aspects, dosage form choice, drug administration considerations and storage and handling advice. In turn, this can lead to potential lack of efficacy or reduced safety of a medicinal product leading to additional special requirements for development of products for these age groups. The underlying complexity of pharmacology and biopharmaceutics in neonates, especially in preterm babies, can lead to altered and variable pharmacokinetics and pharmacodynamics even compared to that in young babies. A host of other physiological factors such as gastro intestinal (GI) pH, body surface to volume ratio, body fat to lean tissue ratio are also different and are known to change rapidly with time. Additionally, the skin barrier may not be fully formed, and respiratory function may be immature. For example, neonates have reduced gastric emptying, intestinal transit time and surface area, and transporter immaturity, which have relevance for oral drug delivery. This immaturity of organ and function is more profound and impactful in preterm infants. Even if born at term and ready to grow outside of the mother’s womb, most organs and their functions are still immature. Įach year, some 15 million babies arrive in the world, more than one in 10 babies are born prematurely, according to the report ‘Born Too Soon: The Global Action Report on Preterm Birth’ (2012). The neonatal period for preterm newborn infants is defined as the day of birth through to the expected date of delivery plus 27 days. ![]() The neonatal period for term and post-term newborn infants is defined as the day of birth plus 27 days. ![]() Neonates include term, post-term and preterm babies. Neonates are not small adults, and neither can they be classified as small children when it comes to medicinal products and their formulation development. ![]()
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