Rare diseases raise a critical planning consideration for sponsors: how to manage the inclusion of a paediatric population. This can be particularly challenging due to factors such as limited patient numbers, ethical considerations in trial design for children, and the need for age-appropriate formulations.
Around 75% of rare diseases largely affect a paediatric population, which in Europe places additional emphasis on the requirements of the paediatric investigation plan (PIP).
In many cases, sponsors of orphan drugs are going to be studying children and even babies from the outset. They will need to determine what that will entail and how it will impact their protocol design.
Indeed, rare diseases have a devastating effect on children, including the fact that:
- About 70% of rare diseases have exclusively paediatric onset
- Between 50% and 75% of rare diseases begin in childhood
- About two-thirds of rare diseases are found in children
- A total of 70% of rare genetic disorders start in childhood
Engaging with the PDCO
Integral to the PIP is early engagement with the Paediatric Committee (PDCO), which comprises experts in paediatric medicine. The PDCO will want to understand your product and your trial plans and trial design. If your patients are exclusively paediatric, you should be speaking with the PDCO before initiating your trial design so they can assess trial design and endpoints, among other key considerations.
Indeed, the experts at the PDCO can help you enhance your protocol design to ensure you make best use of your data and help you with clinical trial challenges where patient numbers are very limited. Even if the product you are developing is not immediately focussed on children, there may be indications for the same product in the pipeline that will have paediatric populations.
Proper preparation, planning and engagement with the PDCO will not only ensure you meet your PIP requirements. Additionally, it can strengthen your discussions with other health authorities, including your pre-IND meetings with the US Food and Drug Administration (FDA). This can be hugely beneficial to sponsors, since while the FDA does provide guidance in its Pediatric Research Equity Act (PREA), the level of collaborative engagement does not match that offered by the EMA PIP process.
Taking concrete steps for the PIP
The PIP needs to be thought about very differently with rare diseases because of the huge impact these diseases have on children. You need to think how you can best leverage the data you have; for example, consider how baseline natural history data can be used to establish robust endpoints or how early adult data can be used to inform paediatric trial requirements.
Sponsors need to consider age-appropriate dosage forms, such as liquid suspensions and syrups for infants versus size-appropriate tablets for children.
Given the small and highly vulnerable patient populations, sponsors also need to consider non-traditional study designs, such as adaptive trials where accumulated results are used to modify how the trial progresses or leveraging statistical methods to compare trial outcomes to historical data.
Tapping into free support
All sponsors submitting a PIP are entitled to a free consultative process with paediatric experts at EMA. They can take advantage of early validation of study plans, addressing gaps that may delay approvals and simply just engaging with experts in the field.
Furthermore, the experts at PDCO are the same as those on the Committee for Medicinal Products for Human Use (CHMP). Engaging with them and building a rapport early on allows them to get to know your product and how your science works, which can result in a smoother progression to marketing authorisation discussions later.
Finally, remember that your goal is the same as that of the EMA: to get safe, effective, well-studied treatments for children, particularly in high unmet need areas of rare disease. To achieve this, sponsors should focus on early engagement with the PDCO, leverage baseline data effectively, explore innovative trial designs and ensure age-appropriate formulations. These steps will not only support regulatory compliance but also contribute to meaningful advancements in paediatric healthcare.
Proper preparation, planning and engagement with the PDCO will not only ensure you meet your PIP requirements, but can strengthen your discussions with other health authorities.