Early paediatric investigation plan (PIP) submissions – an unnecessarily bitter medicine?
In the European Union (EU) Paediatric Regulation, the first PIP submission is requested early in the clinical development program. The regulation states it should be submitted at the end of phase 1 clinical studies, while the European Medicines Agency (EMA) website gives somewhat more flexibility, requiring a submission before phase 3.
The rationale for an early submission is the possibility of identifying new medicines where pediatric studies should take place early, in parallel with adult drug development, due to a large unmet pediatric medical need. The disadvantage of early PIP submissions is that there is a need to substantiate a development plan based on the limited information available at that time. In addition, as not all drugs under development make it to phase 3, and as early PIP decisions may result in many revisions, the procedure uses significant industry, EMA, Pediatric Committee (PDCO), and EU member state resources.
Thus, the idea for the stepwise PIP (sPIP) pilot was born. But which drug programs should it be used for, and when should it be created during clinical development?
While there may be limited information available for particular submissions, the EMA proposes to test the concept through a pilot of the sPIP consisting of only a partial development program. This is conditional on the sponsor developing a full PIP once the critical information has become available.
The requirements for participating in a sPIP submission haven’t been fully defined as the pilot will compose a learning phase. Very rare pediatric diseases are highlighted as well as drug candidates with an unknown mechanism of action, potentially affected by ontogeny. “Medicinal products with multiple development options to address significant unmet pediatric need in several pediatric indications where adult data are lacking” is also mentioned as a potential type of product where an sPIP could be suitable. In addition, the EMA foresees suitability of drug candidates for the sPIP program if critical PIP elements, such as study design, population/age groups and main endpoints are difficult to define.
The sPIP project starts in early 2023 with 8 voluntary sPIPs adopted for initial opinions. For candidates, a dedicated pre-submission meeting with the assessment team is strongly recommended. Support is provided and contact with the Paediatric Medicines office is mandatory. The parts of the PIP which cannot yet be defined should be well justified. Show when the missing information will be available for any dependencies. PIP modifications are planned based on milestones/timelines as agreed by the PDCO. Data needed to define key elements of the sPIP will be outlined and agreed upon. Compliance checks are done as before. The goal is unchanged: a complete PIP is needed for sponsors to gain prolonged marketing exclusivity under the Paediatric Regulation.
We applaud EMA for this initiative and look forward to helping clients interested in this approach and to the knowledge this project will generate. The sPIP pilot holds the potential to further optimize the EU Pediatric Regulatory Framework and pediatric drug development.
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