Expert comment: EMA’s stepwise PIP – Toward regulatory integration after successful pilot

Following the positive review of the stepwise paediatric investigation plan (sPIP) pilot, first published in February 2026, the European Medicines Agency (EMA) is planning to conclude the pilot phase and integrate the sPIP framework into the existing paediatric regulatory landscape on a voluntary basis. A conventional, i.e., fully defined, PIP at initial submission should however remain the primary regulatory route, with the sPIP as a complementary mechanism intended for exceptional and justified cases.

Background

Under the EU Paediatric Regulation, a paediatric investigation plan (PIP) must be agreed with the European Medicines Agency (EMA) early in the life cycle of a medicinal product. Typically no later than the completion of  pharmacokinetic studies in adults or before initiation of any trials in paediatric participants. The goal of a PIP is to ensure that the necessary data to support the use of medicines in children are generated in a timely manner. However, because PIPs are established at an early development stage, they often need to be designed despite scientific uncertainties that may only be resolved as more data emerge.

In most cases, applicants are nevertheless expected to present a full, coherent PIP at the initial application. Yet in some cases, such as for innovative therapies or products developed for very rare paediatric conditions, applicants may lack critical information needed to determine essential study design elements at such an early stage.

These challenges prompted the EMA to launch the stepwise PIP (sPIP) pilot. The aim was to explore whether a stepwise and structured milestone‑driven approach could provide sufficient regulatory flexibility without compromising the high standards of paediatric development.

Summary of main findings following the adoption of the first 8 sPIPs

Between Feb 2023 and Jan 2025, 27 sPIP eligibility requests were received, mainly in rare genetic diseases and oncology, 15 sPIPs were subsequently submitted, and 8 sPIP opinions adopted. Most ongoing sPIPs are scheduled for completion between 2029 and 2035.

The majority (62.5%) of the 8 agreed sPIPs did not contain a partial waiver. This differs from the usual practice for standard PIPs, where waivers for specific age ranges are very frequently granted. This reflects the predominantly paediatric focus of the development programmes included in the sPIP pilot.

Clinical studies were included in all of the 8 agreed sPIPs, for a total of 21 clinical studies (2-4 per sPIP). Quality studies were included in 6 of the 8 sPIPs. Non-clinical studies were included in 5 of the 8 sPIPs, with one non-clinical study identified as critical for a go/no-go decision.

The most commonly undefined key elements in the sPIPs were sample size (57.1%) and dosage (47.6%). Other undefined elements included, in decreasing order of frequency: endpoints, statistical analysis, study duration, and control.  

Procedure-wise, the majority, but not all, of the sPIP submissions were preceded by a pre-submission meeting. The median time from eligibility request to pre-submission meeting was 1.5 months (range: 5 days to 6 months, largely influenced by scheduling challenges). The interval between pre-submission meeting and sPIP submission varied from 1.5 to 5 months, and it took 10 to 14 months from sPIP submission to opinion.

Conclusion & next steps

• The pilot demonstrated both the feasibility and utility in regulatory practice of the sPIP procedure, which offers a structured yet flexible approach.
• The project is therefore planned to transition from the pilot phase to an established regulatory procedure, with development and publication of updated guidance documents.
• The sPIP procedure fosters early engagement and close interactions between applicants and the EMA.
• The sPIP framework is particularly suited to programmes targeting unmet paediatric medical needs in rare diseases; it should not be viewed as a general alternative to standard PIPs.
• The time from sPIP submission to agreement was similar to that of conventional PIPs.
• Additional procedural challenges are however expected in the future with regards to the planned iterative PIP modifications that are a hallmark of the milestone-driven sPIP procedure. The inherent complexity of sPIP updates may be difficult to accommodate within the 60‑day/no‑clock‑stop modification procedure. Pre-submission meetings will therefore continue to play a critical role and may become more frequent.
• The EMA plans to monitor long-term outcomes (e.g., compliance with agreed milestones) to assess whether the sPIP approach helps accelerate overall the development and availability of medicines for rare paediatric diseases.