During our conversations with clients from the United States, we often find there is a misunderstanding about the paediatric investigation plan (PIP). Many see the PIP as simply a document that is part of the clinical trial application process or marketing authorisation application interactions with the European Medicines Agency (EMA).
This confusion stems from the fact that the Food and Drug Administration’s (FDA) paediatric process emphasises ongoing amendments rather than formal agreements like the PIP.
The PIP as a contract
So, it is important to understand that the PIP is a contract that states your paediatric research plans. You agree to a study design and the inclusion of certain age subsets, as well as other criteria in the PIP, and it is a requirement that you follow the PIP exactly.
The Paediatric Committee (PDCO) expects sponsors to adhere to the agreement or come back to them before submitting their MAA to provide updates and explain what is feasible and, if modifications are needed, where and why, and how gaps in patient populations will be addressed later.
There are steps companies can take to avoid problems and delays arising during the MAA. These include:
- Be prepared to justify decisions. For example, if your initial studies exclude neonates due to safety concerns, make sure you provide a plan to evaluate this population later, or justify their exclusion.
- Requesting a compliance check in advance to avoid problems later. A compliance check will include assessing study endpoints, pharmacokinetic requirements for children, ethical justifications for certain procedures, such as placebo use in paediatric populations and age-appropriate formulations. A compliance check may reveal issues, such as insufficient pharmacovigilance planning for certain age subsets, which can then be addressed proactively.
- Discuss plans to defer studies. It may be that you are struggling with recruitment for a certain age subset or follow-on paediatric studies that you want to defer or partially defer until after your MAA or conditional marketing approval. Regardless of the reason, if you are looking to defer studies, make sure you discuss that with the PDCO and get agreement in advance.
- Be aware of likely ramifications of deviating from the agreed process. Sponsors that diverge from the PIP without consultation risk delays in MAA validation, additional submission cycles to rectify gaps, or potentially even rejection of the application in serious cases.
Communication is key
While the PIP is a contract, it can be adjusted, but this requires communication with EMA to justify any modifications. For example, if you struggle to recruit patients from specific age groups, you can propose alternative strategies, such as extrapolating data from adjacent age groups or using real-world evidence.
It is fair to say that the PIP requirements are not as explicit as they could be, which is why we find sponsors from outside the EU are not always clear what EMA and the PDCO will require.
Understand the compliance check process
Nevertheless, the PDCO will be strict when carrying out the compliance check. For example, we have seen pushback from the PDCO when there are slight differences in terminology in terms of population of the trial compared with what was listed in the PIP, which has resulted in lengthy delays for approval.
That is why we spend time with clients explaining what is required, how to manage those requirements and when and how to make adjustments to your PIP.
The PIP is a contract that states your paediatric research plans. You agree to a study design and the inclusion of certain age subsets, as well as other criteria in the PIP, and it is a requirement that you follow the PIP exactly.