Optimising Paediatric Studies in Clinical Drug Development

Drug development in the world of paediatric medicine is hitting a wall. Without developing new strategies, patient recruitment and retention will continue to plummet and jeopardise lives. Innovative changes to clinical trial design and learning about patient incentives have opened the door to the possibility of securing successful paediatric studies. Future developments are prioritising paediatric development with new legislation, but also incorporating adolescents into clinical trials within paediatric medicine creates the possibility of minimising the need for children to take part.

Paediatric studies are essential when advancing therapeutic treatment for developmental and acquired illnesses. However, it remains an on-going challenge to develop innovative, accessible drugs for rare paediatric diseases due to challenges in recruitment and retention. The recruitment of children in clinical trials is invaluable due to their unique metabolic pathways, organic function and general physiology. As a result, paediatric studies are important to accurately represent the pharmacokinetic action of drugs within children, to optimise their efficacy.

Nevertheless, due to various factors including unpleasant procedures, repeated hospital visits and side effects, patient retention remains an issue. Patient recruitment is also difficult due to ethical consideration of whether the subject understands the trial and how consent is validated. As a result, this greatly impacts the progression of therapeutic developments for paediatric conditions. New strategies are required to overcome these barriers, and improve the number of successful paediatric studies while supporting drug development.

Challenges of paediatric studies

Low recruitment is a common but costly issue in clinical trials that halts the progression of research. An early study by Hudson et al. (2016) investigated recruitment statistics for life-threatening paediatric illnesses and highlighted a key problem within this demographic. One third of the included studies recruited fewer than 50% of eligible participants. 

Two of the main reasons highlighted included the patients’ lack of interest and negative perceptions of potential participation. Changing perceptions of clinical trials is a  reoccurring challenge with child-based studies. In terms of the parents’ main agenda, they prioritised clinical benefit, child safety and the future application of the research. Recruitment strategies within this population are reported very little, suggesting further research is required to determine targets for increasing participation across trials.

Psychological trauma is a common occurrence with paediatric patients and one of the reasons for poor participant retention. The frequent hospital visits associated with uncomfortable, painful procedures result in a fear of the clinical environment. The problem with this is that typical subjects required for paediatric studies are often these patients who have yet to succeed with treatment. Patients who have already had many negative experiences associated within clinical settings are at risk for dropping out mid-trial. Children, however, thrive greatly with reward-based situations. More appropriate incentives tailored to the participants could be implemented in paediatric studies to maximise the chance of retention. Previous attempts with financial incentives in adolescent clinical trials have failed to impact recruitment significantly. Clinical trial drop-outs are also associated with randomised controlled trials (RCTs), where patients do not want or feel uncomfortable with blinded options.

How significantly do these challenges affect drug development programmes?

The impact of these challenges continues to compromise drug development for paediatric-specific diseases. Oncology is an area particularly in need of successful paediatric programmes to better target childhood cancers. A key example is the continuous development of treatment against leukaemia, present in both adults and children, but limited research into paediatric brain cancers like diffuse intrinsic pontine glioma.

Addressing the challenges

Due to these challenges, the patient pool for paediatric studies remains limited. Clinical trials often take place across many sites around the world with minimal recruitment. As result, new operational strategies and innovative methodologies are being developed to address these issues.

Strategic monitoring of potential risks is a key part of refining paediatric clinical trials. Due to their physical and mental vulnerability, it is essential clinical research organisations go above and beyond to minimise risks to participants. Risks identified include physical harm (due to treatment), discomfort, and embarrassment. A key risk that may not be as easily monitored is breach of privacy and confidentiality. It is important to disclose this risk to the subject’s consenting adult, as children typically wouldn’t be able to understand the use of their personal data. Early planning and approaches with regards to dosage and safety is a prime example of minimising risk.

Novel trial designs such as the informed complementary trial (PICT) have been suggested to address the main weaknesses in the traditional RCTs. RCTs are the gold standard for comparing interventions in healthcare. However, they are flawed when “patients have strong preferences that directly influence treatment decision”. This affects the external validity that relies on one sample representative of the whole patient group. RCTs in the context of paediatric trials may be unable to recruit patients who do not accept random allocation to intervention.

In the PICT design, a single study comprises different trials to which patients/families are given the opportunity to choose the right one for them. They can select a trial with all available treatment options, or a trial with treatment options that exclude the option that may be subject to stronger preferences. The benefit of this design highlights the shared decision-making required in research. Furthermore, it addresses the dilemma that patients and families face when choosing to give consent to receive an “allocated treatment” or be excluded. This is also comprising the validity of research in a practical sense, and ethically in terms of this ‘shared decision-making’.

Future strategies

As of 2019, legislation requiring specific paediatric development plans, including the Initial Paediatric Study plan and Paediatric Investigation Plan, were created. Despite only existing (in completion) in the US and EU, these represent a significant step forward in creating a more systematic, thorough approach to operating and monitoring paediatric clinical trials.

Furthermore, research has demonstrated the significance of engaging children with the trial process. Originally, information of high importance regarding ethical requirements was given directly to the parents/legal guardians. The latest regulations, however, highlight the importance of acknowledging the wishes of the subjects, with regards to their participation and engagement.

Incorporating adolescents into clinical trials is another alternative concept to optimise paediatric research by limiting their participation. It is suggested to be “…complementary to existing paediatric and adult drug development approaches and should not replace or delay them; rather it increases opportunities for adolescents to be included in early-phase trials”.

Further research is required to better identify the challenges behind the poor recruitment and retention paediatric studies. From here, successful studies will continue to support essential drug development programmes, and offer hope for treating rare paediatric diseases.  

Charlotte Di Salvo, Lead Medical Writer
PharmaFeatures