An estimated ninety percent of drugs used to treat our youngest patients, e.g., in neonatal care units in pediatric hospitals, are used off-label. This means that the safety and clinical efficacy of these drugs have not been scientifically tested or approved by a health authority. The situation is less dire for children and young adults, but there is still a substantial need for better and more age-appropriate pediatric formulations for children. Why is it that we don’t have more and better medicines for children? It all starts with the fact that children are not small adults. Their body, their metabolism, their ability to take medicines, e.g., chew a chewable tablet or swallow an oral tablet, are all developing and changing over time. Consequently, multiple different products/dosing regimens for different age groups must be developed. This fragments an already small market for pediatric products. Also, who wants to pay more for a child-friendly product when you can simply crush a cheaper adult tablet?
The problem of forgetting children when developing new drugs or improving existing ones has been widely recognized. In the European Union and the United States, governments have put forward mandates for pharmaceutical companies to study new drugs for children, unless it wouldn’t be safe to do so. Companies must develop formal plans (the so-called Paediatric Investigational Plans in the EU and Pediatric Study Plans in the US) and get those approved by the corresponding health authorities. If commitments to those plans have been met, the originator companies are rewarded with additional market exclusivity for the adult product. It is noteworthy to add that, if those pediatric commitments are not met, health authorities can delay the approval of the corresponding adult product. This “carrot & stick” concept has been in place now for almost two decades and has resulted in a significant increase in pediatric labels (indications) for approved drugs and made more age-appropriate formulations available to our young patients. However, developing pediatric formulations and conducting pediatric clinical trials remain very challenging tasks and often surpass the capacities of small/start-up companies focusing on innovative product and new drug delivery concepts. For formulation scientists, expert groups like the International Consortium for Innovation and Quality in Pharmaceutical Development (IQ) or the European Paediatric Formulation Initiative (EuPFI) offer a pre-competitive space to discuss and learn about best practices. On the clinical side, specialized clinical trial networks provide valuable tools and access to clinical sites experienced in pediatric studies. For off-patent products, the above-mentioned incentives are lacking. This is particularly true for many tropical childhood diseases with only older drugs or no therapeutic options available. Over the past two decades, several so-called Product Development Partnerships (PDP), e.g. the “Drugs for Neglected Diseases Initiative (DNDi),” have emerged. Supported by philanthropic funding organizations, these PDPs are increasingly developing better medicines, and recently also new chemical entities, for children. The World Health Organization (WHO) publishes and keeps updating a list of essential medicines for children. Not surprisingly, a number of these compounds don’t have adequate age-appropriate formulations. To focus the limited available resources, WHO has developed a pediatric prioritization (PADO) process to select the most important drugs and, through the “Global Accelerator for Paediatric Formulation” (GAP-f) network, provides guidance for further formulation work.
On the innovation side, new technologies, e.g., the ones based on mRNA with novel drug delivery systems such as lipid-nanoparticles, have resulted in a substantial innovation boost, as evident at the recent annual meeting of the Controlled Release Society (CRS) in Bologna, Italy. Along with the new drug delivery concepts also come new excipients that need to be toxicologically evaluated before they can be applied to pediatric formulations. On the oral pediatric formulation side, formulators focus on oral dispersible tablets, pushing the age boundaries further down for mini-tablets (2 mm or less in diameter) and oral dispersible films. For orally delivered products, still representing most pediatric medicines, the bitter taste remains a big challenge. The traditional ways of adding sweeteners and flavors or coating the active pharmaceutical ingredient for taste masking may not work in all cases. The recent discovery of bitter blockers—we have about twenty-five different bitter receptors on our tongue—may represent an interesting future option for pediatric formulations, although more research is still needed. Since children don’t like needles, there is interest in the advancement of needle-free routes of administration, like the microneedle array patches for vaccines and other biologics.
While the above-mentioned requirements and incentives are to stay, more is needed so that all children have access to age-appropriate medications. First, better commercial incentives are needed. Reliance on the donation programs offered by the pharmaceutical industry or the philanthropic sponsoring of new product development programs cannot be considered as a long-term solution. Second, more global harmonization of regulatory requirements is needed to streamline the development and approval processes, thus shortening the time it takes from the initial approval of a new drug for adults until the corresponding pediatric products are approved. Third, a change in mindset is needed so that formulators will think pediatric formulations first before creating the corresponding adult formulation. This could result in synergies, but also help at the other end of the age spectrum, improving the acceptability of oral dosage forms for the geriatric patient population. While this may sound like too much change needed, it is up to all of us, wherever we stand in development, manufacturing, or distributing of medicines, in their approval process or in policy making, to please not forget our youngest patients!
