A Changing Landscape

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For much of the 20th century, research, regulations and formulation development have focused on treating diseases in adults, leading some to describe children as “therapeutic orphans” (1). With fewer options available and with dosages and administration routes that failed to satisfy the pediatric demographic, there was a clear need – and a gap in the pharmaceutical market. Here, Matt Ling, Director of Scientific Services, Oral & Specialty Delivery, and Andrew Parker, Senior Program Manager, Early-Phase Development, Oral Drug Delivery – both at Catalent – consider the progress the industry has made in the development of pediatric formulations and the issues that developers still face. And perhaps most importantly, they define the steps that need to be taken to bring truly child-optimized medicines to market faster.

How has the industry changed to make pediatric formulations a priority?

Andrew Parker: A decade ago, regulatory changes in the industry fostered a shift in attitude towards pediatric development. Before this, due to the limited potential revenue returns for large pharma, pediatric medicines were viewed with lower priority than other competing drivers, such as “ever-greening” a current adult formulation portfolio by looking at second generation formulations or alternative delivery technologies. In Europe, incentives are now in place for companies to comply with the regulatory requirements of a Pediatric Investigation Plan or PIP (a medicines development plan to support the authorization of a medicine for children). PIPs must be drafted and submitted from late Phase I, and subsequent marketing authorization applications must include the results of studies conducted in the PIP. Applications that comply with this can be eligible for a six-month extension to their licenses (two years for orphan drugs). And so now the development of a pediatric drug has both strong financial and regulatory drivers. Similar regulations exist in the USA and, as of 2017, the RACE for Children Act authorizes the FDA to compel companies developing cancer drugs to also develop their drugs for children, if the molecular target of the drugs under development are relevant to a pediatric cancer. I think this really emphasizes the importance of increasing the availability of medicines to the youngest patients.

What are the most important developments of the last decade?

Matt Ling: One of the most important developments in the last decade has been the increased “noise” level, which has resulted in more companies devoting time to both development of pediatric drugs and, as a by-product, engaging in an increased number of conferences and publishing more peer-reviewed literature. This increased activity is also reflected in the number of joint endeavors between academia and industry, which are addressing a variety of issues; for example, developing and refining new taste masking technology, creating new methodologies to assess taste, and developing improved in vitro and in silico approaches to simulate and predict the likely exposure of a pediatric formulation in children.

In the formulation space, mini tablets surfaced as a developable and acceptable platform for pediatric drug delivery. Typically only 2-3 mm in diameter, minitablets may be dosed individually or as multiple tablets when mixed with soft foods. Mini tablets can be quick to develop because they adapt the adult tablet presentation. They can also be used where bioavailability enhancing technologies are required, such as for amorphous solid dispersions. Several studies have been performed to investigate the acceptability of administering multiple mini tablets to infants and children, demonstrating favorable acceptability when compared with a standard syrup formulation (4).

What are the key challenges of developing medications for children?

Ling: The most important challenges are ensuring the dose level is scaled correctly for the intended age and weight of the patient, and optimizing the formulation to give the correct release profile in the child. These challenges are compounded by more widely varying levels of absorption in children compared with adults. For example, if transit time is slower and solubility is higher than expected, there is potential for the absorbed dose to be higher than predicted, introducing the risk of toxicity. Alternatively, if transit time is fast and solubility is low, then drug absorption will be lower than predicted and there will be a risk of ineffective dosing. These attributes can vary significantly in children of different age groups. The physiological differences between adults and children demand scientifically-justified dose scaling to support safe and efficacious dose selection in the pediatric population. Formulators, therefore, need to understand that the correlation between drug exposure and body weight is not always linear. 

To date, oral solid dosage forms have remained the formulation of choice within the pharmaceutical industry, due to the established advantages of long-term stability, ease of supply chain and low cost of manufacturing. But the degree of dose flexibility or dose adjustment required for a given product should influence the design of its formulation and give formulators pause for thought when developing products best suited to children.

In addition to establishing an effective dose level for children, issues of taste, acceptability and compliance in administering the dose as intended are important aspects that will often dictate the formulation strategy for the product. Most APIs have an undesirable taste and compliance failures are often manifested by a child spitting out the medicine immediately after dosing. Taste masking is, of course, an option to overcome this, often involving excipients such as coating polymers, sweeteners or flavorings. Guidance issued by the EMA in 2013 states that patient acceptability must be an integral part of pediatric drug formulation development. However, regulatory guidance is less clear on how acceptability is measured. Different approaches have emerged, with some research citing methods like the Visual Analogue Scale (a psychometric response scale) as a potential method for assessment, while others refer to the Hedonic scale (a test in which responses are rated on a scale from “dislike extremely” to “like extremely”) as another potential form of assessment. Though these assessment methods have their benefits, they also create disparities in the ways that acceptability can be accurately measured. More recently, efforts have been made to standardize practices with papers published to try and provide a more harmonized assessment (5).

During the development of the formulation, assessment of the taste can present another challenge. The e-tongue, an instrument that measures and compares tastes, presents one in vitro method to assess the scope of the taste challenge. An e-tongue uses an array of electrodes to compare the taste pattern of the API to human calibrated standards for tastes – sweet, sour, bitter, salty and umami. It can also be used to compare the similarity between taste-masked formulations with or without the API to determine the degree of masking that can be achieved. Recently, more sophisticated preclinical models have been developed that can be used to assess how animals, such as rats, will respond to the presence of the API at different concentrations in drinking water. The results from such studies have been found to correlate well to similar studies in human volunteers (6).

How important is collaboration to the development of novel pediatric drugs?

Parker: Collaboration is always an important component when trying to either solve pan-industry challenges or agree on general recommendations for scientific approaches to industry needs. All voices need to be heard – and agreement on approaches is sometimes difficult to reach. Several organizations have been established to try and provide a vehicle for engagement and dialogue on the topic of pediatric medicines. The European Paediatric Formulation Initiative, a consortium working in a pre-competitive way on pediatric drug formulations, is one example of this. The group is made up of pharmaceutical companies, hospitals, and academics, who work closely with one another to resolve scientific, regulatory, and technological issues associated with pediatric formulation development. Through information sharing, lobbying, and building cross-industry networks they aim to foster improved awareness of the current challenges and opportunities faced by pediatric drug developers.

Describe your ideal future for pediatric medicines...

Parker: A future where the pediatric development strategy is incorporated at the outset (in other words, the preclinical phases) of any development program, rather than an add-on during clinical stages. Such an approach could shorten a pediatric medicine’s time to market, to the benefit of today’s children and tomorrow’s adults.