Sandra Blumenrath and Ronald Portman provide an overview of the challenges of developing medicines for children, and explore recent innovations that will spur advancements in the field

Paediatric drug development has seen a significant paradigm shift in recent years. Globally converging policy reforms, pragmatic solutions to the complexities of paediatric clinical studies, and an evolving conviction that children have the right to benefit from scientific progress rather than to be protected against it have all contributed to improvements made in the paediatric drug development process. Yet, it remains challenging to develop and provide quick access to innovative, high-quality medicines that are safe and effective for children, especially in rare paediatric diseases. This article provides an overview of these challenges and explores recent innovations that will spur advancements in paediatric drug development.

Addressing the Need

Ignoring paediatric considerations in drug development is no longer an option. More than 50% of drugs used in children and more than 90% of drugs used in newborns lack proper paediatric labeling (Wharton et al. 2014). To ensure that drugs are assessed for children, paediatric provisions exist in several regions, including Canada, Australia, Japan, the US, and Europe. Specifically dedicated, complete paediatric legislation, however, currently only exists in the US and the European Union (EU) (Thomsen 2019). Here, legislation requires specific paediatric development plans, such as the initial Paediatric Study Plan (or iPSP) and the Paediatric Investigation Plan (or PIP), respectively. In the US, for example, two companion legislation acts – the Paediatric Research Equity Act (PREA) and the Best Pharmaceuticals for Children Act (BPCA) – and the FDA Safety and Innovation Act (FDASIA) have significantly increased the number of drugs with paediatric labeling (Christensen 2012, Yen et al. 2019). More funding and scientific advances in areas of special benefit for children, such as platforms for cell and gene therapy, have also spurred the increased focus on paediatric clinical trials and paediatric products. But with this new research environment also comes a unique set of challenges for today’s drug developers.

Challenges of Paediatric Drug Development

The challenges of paediatric drug development are manifold and include ethical, methodological, operational, and financial limitations. Developing medicines for paediatric populations is essentially comparable to developing orphan drugs. With at least five paediatric sub-populations—based either on age or developmental stage or, more recently, on rapid changes in pharmacokinetics and pharmacodynamics (PK/PD) (Job et al. in press)—there are very few paediatric patients with a given disease: A single disease and the corresponding treatment response patterns may manifest themselves slightly differently in each sub-population, and inclusion/exclusion criteria further narrow the pool of eligible patients for study enrollment.

Because of the small patient pool, paediatric studies have high infrastructure needs, requiring trials to take place across multiple sites and countries, often with an average of only one to three patients per site per year. Many trials fail or stall, and those that do succeed take too long to complete, resulting in nearly a decade between indication in adults and paediatric labeling. And, despite new regulation, systematic guidelines and methodologies are still lacking. What’s more, although new regulation has increased the inclusion of children and adolescents in paediatric drug development, paediatric trials are still not widely accepted by society for fear of exposing children to uncertain treatment effects.

Luckily, paediatric product development has matured over the past years. Compared to only a decade ago, clinicians, developers, regulators, and patients/parents have gained substantially more experience with innovative paediatric clinical trial design (including paediatric extrapolation) and paediatric formulation. The true partnership of this paediatric drug development community is therefore much better equipped to address both remaining and new challenges.

Addressing the Challenges

Regulatory directives to conduct paediatric clinical trials have spurred innovation by the paediatric community at various stages of drug development. Several methodological and operational innovations leverage existing information and infrastructure to build effective paediatric studies, including:

Paaediatric extrapolation

Pharmacometrics (simulation and modeling), often with the use of Bayesian statistics

Innovative clinical trial designs

Real world evidence

Inclusions of adolescents in adult clinical trials

Global clinical trial networks

Tissue agnostic approaches to drugs with multiple potential indications for the mechanism of action

Early planning, however, is essential for the success of these innovative approaches.

Early Approaches: Dosage and Safety

With paediatric extrapolation, efficacy data from adult studies are extrapolated to paediatric patients if the disease course and response to treatment are sufficiently similar between adults and children. Because paediatric patients are considered vulnerable, children should not be enrolled in clinical trials if data from adult studies can sufficiently answer the scientific question at hand. In fact, compared to 20 years ago, extrapolation is becoming the default approach whenever adult and paediatric indications are similar. With this approach, however, early planning during adult development is key if adult trials are meant to be supportive of paediatric drug development.

For example, by including more doses in the adult programmes, especially in biomarker development, it is possible to harness good exposure response profiles in early adult development programmes. Extrapolation of adult efficacy data from studies with wider dose ranges can significantly reduce the amount of additional information that has to be gathered from paediatric trials. The focus of paediatric trials can then shift from dosage and safety to confirming efficacy – an approach that greatly speeds up the development process for paediatric drugs, in addition to reducing risks. Extrapolation is an iterative process, however, so adjustments must be made as more knowledge is gained during the development process.

When there is uncertainty as to whether a drug will indeed work similarly in children, Bayesian statistics can be a powerful innovative analytical tool allowing for smaller, more efficient paediatric studies with valid statistical conclusions (Gamalo-Siebers et al. 2019). Bayesian methodology is essentially a variant of extrapolation; it borrows data from adults and adolescents (including placebo data) and combines them with new paediatric response data to arrive at an estimate for overall paediatric treatment response. Some argue that, if used appropriately, it provides scientifically robust evidence that greatly reduces the sample sizes needed in paediatric studies and other operational challenges, such as trial duration and slow or reluctant enrollment (Gamalo-Siebers et al., 2019).

Similarly, pharmacometrics (simulation and modeling) and Physiologically Based Pharmacokinetics (PBPK) can optimise already available data to inform future paediatric clinical trials (Liu & Ward 2019). Dose-response modeling based on available PD/PK data, for example, allows for a much quicker and more scientifically accurate dose selection for paediatric trials. Finally, the use of real world evidence can be utilised to assess the feasibility of paediatric studies and provide needed data for proper study design selection. RWE combined with clinical trial data confirm analytical assumptions and further solidify the results obtained from these innovative analytical applications.

Although innovative analytics do not replace the need for clinical trials from a regulatory standpoint, they certainly increase efficiency by providing a formal approach for incorporating prior information into the planning and analysis of the paediatric study.

Another step in the right direction is that increasingly more clinical studies enroll adolescents in adult clinical trials. US legislation, for example, now requires that adolescents be included in the early phase studies of most cancer treatments. For many conditions, efficacy and safety data are very similar for adolescents and adults, so the inclusion of adolescents raises less of an ethical concern.

However, some unresolved issues with adolescent studies remain:

Scientific: There are no clear and scientifically validated guidelines as to the proper number of adolescents to include in adult clinical studies. In European clinical studies it has been proposed that adolescents comprise roughly 10% of the study population. But this percentage is by no means an official policy, nor does it pertain to every compound studied. Indeed, if adolescents are included in adult trials, there is an assumption of similarity of disease, dose, and drug response. In that case, a minimum number of adolescents may not need to be set. On the other hand, regulation on adolescent inclusion should not slow down the approval of the adult programmes if it takes a long time to enroll a set number of adolescents.

Operational: Because adolescents are typically not cared for in the same study sites as adults, more sites and investigators are needed to enroll adolescents. Of particular concern are timing issues: Adding adolescents to the adult trial can shorten the time for regulatory reporting requirements which can be a strong disincentive to adolescent inclusion. Despite the issues, there are clear benefits to including adolescents in adult clinical trials. Information from adolescent trials can be used to extrapolate to younger patients. As a result, instead of having to wait an average of nine years between adult programmes approval and paediatric labeling, drugs can be approved much faster and prescribers can gain quicker access to information on dose and side effects.

Later Approaches: Sustainable Paediatric Clinical Trials

A major root cause for why paediatric study programmes are challenging or even fail is due the lack of sustainability of  the ad hoc ‘networks’ formed for each trial. Much fewer children than adults typically need treatment for a particular condition that the adult drug was initially developed for. Therefore, eligible paediatric patients can be few and far between, requiring developers to essentially find as many study sites as patients – a process that is time-consuming, inefficient, and expensive. Stakeholders have long recognised that clinical research networks can break down operational and other barriers and make patient recruitment and clinical studies more efficient (Turner et al. in prep.).

In Europe and the US, two paediatric clinical trial networks – The Collaborative Network for European Clinical Trials for Children or conect4children (c4c) and the Institute For Advanced Clinical Trials For Children (I-ACT) – have joined forces to build the capacity for multinational paediatric studies for all disease areas and all phases of paediatric drug development. These independent, non-profit networks are committed to facilitating high-quality clinical trials that generate enough data to ensure the safety and efficacy of innovative therapies for children of all ages. I-ACT is supported by the US Food and Drug Administration and five pharmaceutical companies thus far. The c4c research network, on the other hand, is a public-private partnership funded and approved by IMI2 (the European Innovative Medicines Initiative) with industry and brings together more than 25 national health authorities and 11 industry partners  as well as many children’s hospitals and patient advocacy groups. One focus of c4c is to promote innovative trial designs that support the development of drugs for rare paediatric diseases and areas of high medical need. Together, these two networks foster sustainable paediatric drug development by helping companies conduct efficient paediatric clinical studies.


Paediatric drug development is complex and difficult. The challenge of obtaining adequate paediatric efficacy and safety data is the major cause for the unacceptable lag between adult approval and incorporating paediatric information in labeling. Children should only be part of clinical trials if adult clinical studies cannot provide the answer, and they certainly should not be enrolled in trials that have little chance of completion. We are therefore faced with a strong ethical obligation to find appropriate alternative solutions to providing children with safe and effective treatments in a timely manner.

Most companies are beginning to pay attention to paediatric considerations early in development, focusing on both possible paediatric formulations and potential toxicity issues as well as on gathering adult data that can assist with paediatric programmes. With the emergence of innovative analytical tools and increased access to global clinical research networks, drug developers are now better equipped than ever to conduct paediatric studies. However, opportunities like these are easily missed if developers don’t consider the operational aspects of paediatric clinical trials very early in drug development.

The next chapter for paediatric drug development must focus on stimulating the development of drugs specifically for conditions that present themselves in particular paediatric ages, especially in the neonatal period (Bucci-Rechtweg & Ward 2019). Although paediatric regulations have been pivotal in moving paediatric drug development forward, not all paediatric sub-populations have benefitted equally. With their unique, transitional physiology, premature and newborn infants constitute a distinct developmental population that differs considerably from older infants. For this population, even fewer therapies exists and nearly all prescribing occurs off-label and without appropriate clinical evidence. So far, attempts at neonatal policy reforms have received only limited traction. Successful policy reforms will have to address financial and operational concerns to stimulate research investments that specifically target neonatal needs.

Sandra H. Blumenrath is a science writer at the Drug Information Association (DIA); Ronald J. Portman executive director, Paediatric Development, Science and Innovation, Paediatric Center of Excellence, Clinical Development & Analytics, Novartis Pharmaceuticals Corporation