EMA Guidance: For stepwise PIPs (sPIPs)

Paediatric drug development remains one of the most complex regulatory areas in the pharmaceutical landscape. Scientific uncertainty, evolving clinical insights, and gaps in early evidence often make it difficult for developers to design complete paediatric programmes at the initial stages of development.

Recognising these challenges, the European Medicines Agency (EMA) has introduced a specialised mechanism known as the stepwise Paediatric Investigation Plan (sPIP), formally explained in the guidance Guidance for stepwise PIPs (sPIPs).

A Paediatric Investigation Plan (PIP) is a structured research and development programme describing how data will be generated to support the authorisation of a medicinal product in the paediatric population. It outlines clinical studies, timing, measures, and age subsets to ensure children have equitable access to appropriately studied medicines.

According to the guidance, a PIP must typically be submitted no later than the completion of adult pharmacokinetic studies, or, for paediatric-only products, before paediatric trials begin. The PIP is evaluated by the Paediatric Committee (PDCO) and results in an EMA decision in line with Regulation (EC) No 1901/2006.

What Exactly Is a Stepwise PIP (sPIP)?

An sPIP is a modified regulatory pathway where only a partial paediatric development programme is agreed at the initial stage, with the remainder to be completed later as more evidence emerges.

The EMA acknowledges that certain products—due to novelty, rarity, or scientific immaturity—cannot support a fully detailed paediatric plan at the beginning. Examples include:

• Medicines for newly identified paediatric diseases

• Products with mechanisms of action not yet fully characterised

• Therapies with multiple development pathways addressing high unmet paediatric need

• Situations where adult data are insufficient to extrapolate paediatric decisions

These scenarios may make it impossible to define fundamental elements such as study design, endpoints, dose selection, or age subsets.

Thus, an sPIP is granted only in exceptional cases, and the applicant must justify why elements cannot be determined yet and when they expect to have the necessary data. Even though an sPIP is partial, it is not an empty placeholder. According to the guidance, every sPIP must still include:

• The paediatric condition

• A preliminary outline of planned studies, based on available scientific evidence

• A PIP completion date

• An overarching paediatric development strategy

• Milestones for when missing elements will be submitted

This ensures regulatory predictability and avoids excessive ad-hoc modifications.

The guidance states that an sPIP should only be used when critical PIP elements cannot be defined, even with the best available science.

Examples of elements that may be too uncertain include:

• Study Designe.g., uncertainty regarding control group, randomisation, or blinding.

• Population Definitione.g., inability to define age subsets because disease progression differs significantly from adults.

• Primary or Secondary Objectivese.g., absence of validated biomarkers or pharmacodynamic endpoints.

Applicants must provide scientific justification explaining why defining these elements is not feasible today and describe dependencies between studies.

All PIPs—whether conventional or stepwise—use the same template. However, sPIPs must include additional explanations in specific sections:

1. Application Summary

• High-level explanation of which elements are missing

• Scientific justification for stepwise approach

• At minimum: condition, preliminary study outline, and completion date

2. Section 2 of the PIP Template

• Comprehensive justification for why certain studies or study elements cannot yet be planned

• Detailed discussion of existing information or knowledge gaps

3. Section 3 (Waiver Considerations)

• If waiver details (e.g., age cut-offs) cannot yet be defined, reasons must be clearly explained

• Describe how necessary data for defining waiver elements will be generated

4. Section 4 (Paediatric Development Programme)

• Include a high-level strategy even if details are missing

• Provide commitments to future modification timelines

• Outline how missing data will be collected

Once a stepwise approach is accepted, the missing elements must be added through the established PIP modification procedure. Once all elements are complete, the sPIP undergoes the same compliance check process as a full PIP. Only a fully completed PIP (not a partial one) can meet the requirements of Articles 36 and 37 of the Paediatric Regulation, which are necessary to qualify for paediatric rewards and incentives.

For more details refer the EMA’s official guidance: Guidance for stepwise PIPs (sPIPs)