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Paediatric Investigation Plan (PIP)

Bringing safe and effective medicinal products to children is a critical goal in modern healthcare. Across the European Union, sponsors must fulfill specific paediatric requirements to obtain or maintain a marketing authorisation for new medicines. Central to these obligations is the Paediatric Investigation Plan (PIP), a development blueprint that ensures clinical data on children is systematically generated. The European Medicines Agency (EMA) introduced this approach to incentivize robust paediatric research under the Paediatric Regulation (Regulation (EC) No 1901/2006). By requiring an agreed plan of studies, the EMA paediatric investigation plan framework helps guarantee that paediatric populations benefit from advancements in pharmacotherapy.

This page explores how the Paediatric Investigation Plan works, the role of the Paediatric Committee (PDCO), possible waivers and deferrals, and how applicants can strategically navigate the EMA PIP to ensure efficient development timelines and compliance. Whether you’re developing an orphan medicinal product or an innovative therapy for an adult indication, understanding the PIP requirements is essential to get a medicinal product authorised within the European Union.

1. The Importance of Paediatric Investigation Plans

1.1 Key Objectives

Generate Meaningful Data: Ensure applicants collect robust efficacy and safety information in children.

Promote Age-Appropriate Formulations: Push for formulations tailored to paediatric use rather than relying solely on adult dosage forms.

Avoid Unnecessary Trials: Allow for exemptions where the product’s mechanism or target disease is irrelevant in the paediatric population.

Facilitate Regulatory Compliance: Embed paediatric studies into the development timeline, reducing last-minute surprises as applicants near marketing authorisation.

1.2 Historical Context and Rationale

Before the Paediatric Regulation came into force, many medicinal products were not studied in children, leading to a lack of appropriate dosing and safety data for the paediatric population. Recognizing this gap, the European Parliament and the Council adopted the Paediatric Regulation to ensure all new medicines are systematically evaluated for paediatric use—or justified via waivers—to improve health outcomes for children.

By mandating a paediatric investigation plan, regulators encourage applicants to consider paediatric clinical development early. The result is better alignment of paediatric and adult trials, a more thoughtful exploration of age-appropriate formulations, and a formal route to gather and publish data that benefits children.

2. Understanding the EMA Paediatric Investigation Plan Process

A Paediatric Investigation Plan is a legally binding plan that must be agreed upon with the EMA’s Paediatric Committee (PDCO). The PDCO is responsible for assessing whether the proposed paediatric studies (or justifications for absence thereof) meet the requirements set forth by the Paediatric Regulation.

2.1 When to Submit a PIP

Generally, sponsors should submit their PIP application to the EMA by the end of Phase I or early in Phase II adult studies. Submitting at this stage ensures paediatric development is planned in parallel rather than being tacked on post-approval. Delayed submission could trigger compliance checks or force sponsors to modify adult trials midstream.
For early guidance, the EMA encourages presubmission meetings and informal discussions to clarify the scope of the paediatric program, the investigation methods, and any potential waivers or deferrals.

2.2 PDCO Assessment and Timelines

Initial Application: The applicant submits the proposed paediatric investigation plan along with relevant supporting documents. One month later, when validation has occurred, the PIP procedure starts.
PDCO Review: The PDCO evaluates the plan over a 60-day timeframe, focusing on study design, age groups, endpoints, feasibility, and more. PDCO sends a List of Issues to the applicant who generally takes 3 months to respond with a modified PIP.
Opinion and Agreement: After 60 days of review of the modified PIP, once the PDCO finalizes its opinion, the EMA adopts the decision in 30-40 days, leading to an agreed PIP. This decision becomes a prerequisite for subsequent marketing authorisation applications in the European Union.

3. Scope of a Paediatric Investigation Plan

The content of an EMA paediatric investigation plan usually covers:

1. Overview of the Disease in Paediatric Populations: Justification for why the condition and/or indication is relevant (or irrelevant) to children. This includes epidemiology, pathophysiology, and special considerations for paediatric subpopulations.

2. Clinical Study Design: Protocol outlines for Phase II and III paediatric trials, specifying endpoints, sample size, and method of age stratification.

3. Formulation Development: Plans for medicinal product dosage forms suitable for neonates, infants, or adolescents if needed.

4. Pharmacokinetic and Pharmacodynamic Evaluation: Proposed methodology to assess how the product’s ADME (absorption, distribution, metabolism, excretion) profile may differ in children.

5. Safety Monitoring: Description of how paediatric patients will be protected and monitored, including adverse event tracking and potential rescue protocols.

6. Study Timelines: Proposed start and completion dates for each investigation.

7. Deferral or Waiver Requests: If the applicant seeks partial or complete exemption from paediatric research. This plan must be specific, reflecting realistic objectives and a methodology consistent with regulatory expectations. Once agreed, the applicantis legally bound to complete the studies according to the final PIP.

4. Waivers and Deferrals: When Paediatric Research Isn’t Feasible

The Paediatric Regulation recognizes that certain products may not be suitable for paediatric populations or may be indicated for diseases that do not affect children. In such cases, applicants can request waivers or deferrals.

4.1 Waivers

A waiver exempts an applicant from conducting some or all paediatric trials. Product-specific waivers might apply if:

  • The disease or condition in question exists only in adult populations and has no clinical relevance to children.
  • There is conclusive evidence that the therapy would be ineffective or unsafe in the paediatric population.
  • The product does not offer any meaningful therapeutic benefit over existing paediatric treatments.


When the PDCO grants a waiver, the applicant is no longer required to conduct the corresponding paediatric studies. These decisions must be published in the EMA’s database, ensuring transparency for healthcare professionals and the public.

4.2 Deferrals

A deferral allows an applicant to postpone part or all of the paediatric studies until after the adult development program has progressed. Deferrals typically apply when:

  • More adult safety data are needed before exposing children to the product.
  • Logistical constraints make simultaneous paediatric and adult trials impossible.
  • Additional formulation work is necessary to create a child-friendly version of the medicinal product.


Marketing-authorisation holders that have received a deferral on a PIP are obliged to submit annual reports to the Agency. These reports should provide an update on progress with paediatric studies in accordance with the decision of the Agency to agree with the PIP and granting a deferral.

5. Compliance Check and Marketing Authorisation

5.1 The Role of the Compliance Check

Before an applicant submits a marketing authorisation application for a new product in the EU, the EMA performs a “compliance check” to ensure the applicant has adhered to its agreed PIP—unless that obligation has been lifted through a waiver or deferral (partial compliance can be needed in some cases).
Applicants can request that a PIP compliance check is carried out before submitting a marketing-authorisation application. Alternatively, compliance checks will be carried out as part of the validation of the application. Applicants are strongly recommended to apply for the compliance check before submission of the marketing-authorisation application to not delay the validation phase. Submitting an application without a compliance check can lead to refusal, delays, or additional queries from the assessor. As non-compliance with the PIP will prevent the validation of the regulatory application, the applicant should consider submitting a request to the PDCO for a modification of the agreed PIP, properly justifying the deviations with the PIP. The PDCO will assess the requested changes and decide whether they are justified.

5.2 Linking PIP Completion to Market Access

Timely completion of the paediatric studies outlined in the agreed plan can facilitate a smoother authorisation process. In some cases, fulfilling paediatric obligations can also lead to additional incentives, such as a six-month extension of the Supplementary Protection Certificate (SPC) and for an orphan, the incentive is a two- year extension to the already granted ten years of marketing exclusivity. This benefit rewards applicants who commit to generating high-quality paediatric data early in their product’s lifecycle, thus extending their commercial protection in return.

6. PIPs for Orphan Medicinal Products

Applicants developing orphan medicinal products—which target rare diseases—are also subject to the Paediatric Regulation but may face unique considerations:

  • Reduced Patient Populations: Rare conditions, especially in children, may pose challenges in enrolling enough paediatric participants.
  • Exemptions for Overlapping Indications: If the orphan indication is exclusively adult (or exclusively paediatric), applicants might seek a product-specific waiver.
  • Incentives Alignment: Orphan designations offer separate benefits like protocol assistance and fee reductions. Combined with a well-structured PIP, applicants can maximize the synergy between orphan incentives and paediatric compliance measures.

7. Post-Authorisation Changes

Even after an applicant secures marketingauthorisation, the paediatric obligations do not disappear. Marketing-authorisation holders are obliged to place their medicines on the market following completion of an agreed paediatric investigation plan within two years of obtaining a paediatric indication.
If the applicant modifies the medicinalproduct, for example, by adding a new indication or changing the formulation—the relevant paediatric studies and commitments may need updating. The applicant should file a variation or an extension to their existing authorisation after having obtained an EMA decision on a new agreed PIP.
Additionally, any new paediatric findings that emerge once the medicinal product is authorised might trigger labeling changes to reflect refined dosing, safety warnings, or newly validated age groups. Maintaining open communication with the EMA ensures compliance and fosters better patient outcomes.

8. Strategic Considerations for an Effective EMA PIP

8.1 Early Engagement and Scientific Advice

Proactive applicants often seek EMA scientific advice before finalizing their PIP. Engaging regulators, especially PDCO members, can clarify scientific expectations, which may vary based on the product’s mechanism of action, disease background, and available paediatric data. This avoids costly protocol changes later and can streamline the entire investigation process

8.3 Coordinating with Global Development

For applicants pursuing approval in the United States or other regions, aligning the EMA PIP with paediatric requests from the FDA or other agencies can reduce duplication. While there are distinct regulatory pathways globally, many underlying scientific principles are similar, allowing data from one region to inform or partially satisfy obligations elsewhere.

8.2 Comprehensive Planning

A robust paediatric investigation plan goes beyond a cursory approach to children’s studies. applicants should present:

  • Detailed Endpoints: Justify efficacy and safety measures tailored to paediatric needs (e.g., growth parameters, cognitive development markers).
  • Feasibility Assessments: Realistic enrollment timelines considering the disease’s prevalence in paediatric populations.
  • Formulation Strategy: Outline plans for taste masking, liquid forms, or other child-friendly designs.
  • Risk Mitigation: Preemptively address potential safety or ethical concerns. The better the planning, the smoother the review and the fewer back-and-forth modifications.

8.4 Handling Waivers and Deferrals Wisely

Strategic use of waivers and deferrals can prevent applicants from conducting studies that are infeasible or clinically irrelevant. However, applicants must justify these requests with robust data or strong scientific arguments. An ill-founded waiver request may cause the PDCO to request additional clarifications, delaying the entire PIP review.

9. Evolving Guidelines and Future Directions

The EMA regularly updates its guidelines and processes for paediatric development. While the core concept of a paediatric investigation plan remains stable, the Agency may publish new policy papers or reflect changes in scientific knowledge in PDCO best practices. Some emerging areas that may shape future PIPs include:

  • Real-World Evidence: Integrating observational data to complement or replace randomized trials in certain paediatric subgroups.
  • Advanced Therapies: Adapting the PIP framework for gene therapies and other cutting-edge modalities targeting paediatric indications.
  • Harmonization Efforts: Closer collaboration with regulators outside the European Union, potentially leading to more streamlined global paediatric programs.


Applicants can stay informed by monitoring the EMA website for updated guidance and participating in public consultations when new regulations or guidelines are proposed.

10. Practical Takeaways and References

  • Start Early: Submit your Paediatric Investigation Plan by the end of Phase I or early Phase II to avoid project delays.
  • Engage with PDCO: Embrace scientific advice sessions to refine your plan and increase the likelihood of a favorable PDCO opinion.
  • Explore Waivers and Deferrals: If justified, they can save time and resources but carefully align your requests with EMA criteria.
  • Maintain Compliance: A compliance check is mandatory before marketing authorisation, so ensure you can demonstrate all required paediatric studies have been completed or legally deferred.
  • Align with Other Regions: Coordinate paediatric development strategies internationally to minimize redundant clinical trials and accelerate timelines.

Conclusion

A well-executed paediatric investigation plan is pivotal to gaining marketing authorisation in the European Union for new medicinal products. By detailing every aspect of the proposed paediatric research—ranging from investigation design to safety considerations, a thorough EMA paediatric investigation plan aligns scientific objectives with regulatory requirements. Moreover, applicants who proactively address paediatric development can enhance therapeutic options for children across diverse disease areas, fulfilling both ethical imperatives and commercial goals.

Through strategic planning, effective communication with the PDCO, and the prudent use of waivers or deferrals, applicants can navigate the paediatric pathway successfully. Ultimately, a robust Paediatric Investigation Plan benefits not just regulators and applicants, but more importantly, the paediatric patients whose lives can be transformed by safer, more targeted medicinal therapies.