Paediatric Investigation Plans (PIPs): The Timeline Driver Many Teams Miss

Developing a medicinal product for the European market requires navigating a complex regulatory landscape where scientific strategy and legal obligations intersect. For developers targeting the paediatric population, or indeed any population where a product might be used in children, the Paediatric Investigation Plan (PIP) is not merely a procedural step; it is a foundational element of the development program that dictates timelines, resource allocation, and ultimately, market access. Many teams, particularly those accustomed to the US FDA system or those emerging from a purely adult-focused indication, underestimate the rigidity and strategic weight of the PIP process under EU law. Misunderstanding the interaction between the PIP, the marketing authorisation application (MAA), and the subsequent paediatric investigation can lead to significant, avoidable delays. This analysis explores the mechanics of the PIP, the nuances of waivers and deferrals, and the practical steps required to integrate this requirement into a global development strategy.

The Legal Foundation and Scope of the PIP

The requirement for a Paediatric Investigation Plan is anchored in Regulation (EC) No 1901/2006, often referred to as the Paediatric Regulation. Its primary objective is to improve the health of children in the EU by ensuring that medicines used for them are subject to high-quality ethical research and are appropriately authorised for use in the paediatric population. The regulation applies to medicinal products for human use, including both new active substances and ‘generics’ or ‘well-established substances’ when intended for a paediatric use that differs from the adult use.

It is crucial to understand that the PIP is a regulatory obligation imposed before a marketing authorisation can be granted for a product that falls under the scope of the regulation. The European Medicines Agency (EMA) and the Paediatric Committee (PDCO) are the central bodies responsible for the scientific assessment of PIPs. While the EMA coordinates the procedure, the PDCO is the specific committee that negotiates and adopts the decisions regarding the PIP. This distinction is important because the PDCO operates with a specific scientific mandate focused exclusively on paediatric needs, often requiring a level of detail and foresight that exceeds standard adult drug development planning.

Triggering the Obligation

The obligation to submit a PIP application applies to any marketing authorisation application (MAA) for a new active substance, or for a product already authorised but seeking a new indication, new pharmaceutical form, or new route of administration. There is a common misconception that this only applies to products specifically developed for children. In reality, if a product is likely to be used in children for the authorised adult indication, a PIP is required. For example, an oncology drug approved for adults may be used off-label for paediatric patients. The regulation aims to close this gap by mandating the generation of paediatric data.

The PIP must be agreed upon by the PDCO before the MAA is submitted. This is a strict condition. You cannot submit an MAA for a product subject to the PIP requirement without a signed-off PIP. The PIP details the measures (pharmaceutical and clinical studies) to be taken to ensure the safety and efficacy of the product in the paediatric population.

Distinction from US Paediatric Study Requirements

Professionals familiar with the US FDA landscape often compare the EU PIP to the Paediatric Study Plan (PSP) and the Paediatric Research Equity Act (PREA). While the goals are similar, the procedural mechanics differ significantly. In the US, a PSP is submitted to the FDA, and discussions occur. However, the EU system is arguably more rigid and formalised. The PDCO is a distinct committee with a specific legal mandate, and the PIP agreement is a legally binding document. The “waiver” concept in the EU is also distinct from the “deferral” or “waiver” in the US. In the EU, a full waiver removes the obligation entirely for specific age ranges or conditions, whereas a deferral simply pushes the timing of the studies to after the adult data is available. The negotiation process with the PDCO is also highly structured, with specific timelines and a requirement for the applicant to engage with the agency early via the “PIP advice” procedure.

Strategic Planning: Waivers and Deferrals

The most critical strategic decisions regarding the PIP revolve around the application for waivers and deferrals. These are not merely administrative requests; they are scientific arguments that must be substantiated with robust data and reasoning. Teams often fail to appreciate the evidentiary burden required to secure these concessions.

Understanding Waivers

A waiver is a formal exemption from the obligation to submit a PIP for a specific product, indication, or age subset. There are three primary grounds for a waiver:

1. Full Waiver: The product is likely to be ineffective or unsafe in the paediatric population. This is often argued for specific oncology indications or rare diseases where the pathophysiology in children is fundamentally different from adults.
2. Partial Waiver: The product is intended for conditions that only occur in the adult population (e.g., Alzheimer’s disease, Parkinson’s disease). However, developers must be careful; if there is a potential “spill-over” effect where the drug might be used in adolescents, the PDCO may reject a full waiver.
3. Waiver for Specific Age Groups: The product is safe and effective in all relevant paediatric age groups except for one or more subsets (e.g., neonates). This requires substantial existing data to prove that the drug cannot be studied or used safely in that specific group.

The risk for teams here is underestimating the PDCO’s scrutiny. For instance, requesting a waiver for neonates based solely on adult data is almost certain to be rejected. The PDCO expects a scientific justification, often requiring preclinical juvenile animal studies or specific pharmacokinetic modelling to demonstrate that the drug is not suitable for that age group.

Managing Timelines with Deferrals

Deferrals are often more strategically valuable for developers aiming for rapid market entry. A deferral allows the applicant to submit the MAA and obtain a marketing authorisation before completing the paediatric studies. The paediatric studies are then completed post-approval, with the marketing authorisation remaining conditional upon the submission of the results.

Deferrals are typically granted on two grounds:

• Availability of the authorised product: The product must be authorised in the adult population first to ensure safety data exists before exposing children to it.
• Therapeutic benefit: The product is intended for a life-threatening or severely debilitating condition, and there is a need for immediate access for adults, while the paediatric development continues.

When negotiating a deferral, the applicant must propose a specific timeline for the completion of the paediatric measures. The PDCO will assess whether this timeline is reasonable. It is a common pitfall to propose a deferral without a concrete plan for how the paediatric studies will be conducted once the adult indication is secured. The PDCO looks for a credible operational plan.

Key Regulatory Obligation: A deferral does not mean the obligation is waived. It is a suspension of the requirement to have the paediatric data at the time of the MAA submission. The applicant remains legally bound to conduct the studies and submit the results by the agreed-upon deadline.

The PIP Submission and Negotiation Process

The process of obtaining a PIP agreement is a formal regulatory procedure with strict timelines. It begins with the submission of an initial PIP application (iPIP) to the EMA. This must be done at least 6 months before the planned MAA submission date for a new active substance, or at the scientific advice stage for other products.

The Role of PIP Advice

Before submitting the iPIP, developers are strongly encouraged to seek PIP advice. This is a specific scientific advice procedure offered by the EMA/PDCO. It allows the applicant to present the proposed development plan and receive feedback on the acceptability of the proposed waivers or deferrals. Engaging in PIP advice is not mandatory, but skipping it is a high-risk strategy. It allows the applicant to identify potential showstoppers early and align the PIP strategy with the PDCO’s expectations.

The Negotiation Phase

Once the iPIP is submitted, the PDCO has 60 days to assess it and provide an initial list of questions. The applicant then has 12 days to respond. Following this, the PDCO has a further 30 days to adopt a final opinion. This timeline is tight. The negotiation often involves detailed discussions on the specific endpoints, age stratification, and non-clinical requirements.

Teams often struggle with the level of detail required. The PDCO does not accept vague commitments. For example, stating that “paediatric studies will be conducted” is insufficient. The PIP must specify the study protocols, the age cohorts, the primary endpoints, and the statistical powering. The PDCO acts as a gatekeeper, ensuring that the proposed studies will actually generate the data necessary for a paediatric indication.

Post-Authorisation Management

The PIP is a living document. Once the MAA is approved, the marketing authorisation holder (MAH) must adhere to the agreed PIP. Any modification to the PIP (e.g., a delay in study initiation, a change in endpoints) requires a formal modification request submitted to the EMA. The PDCO must approve these modifications. Teams often underestimate the administrative burden of maintaining compliance with the PIP post-approval. Failure to conduct the studies or report the results can lead to the suspension of the marketing authorisation.

Interactions with Marketing Authorisation Timelines

The PIP is the single biggest determinant of the timeline for products requiring paediatric development. It is not a parallel track; it is a prerequisite.

The “Stop-the-Clock” Mechanism

One of the most critical procedural aspects is the “stop-the-clock” mechanism during the MAA evaluation. If the PDCO has not yet adopted a positive opinion on the PIP, the clock for the MAA evaluation stops. The MAA cannot be approved until the PIP is agreed. This creates a hard dependency. If a team submits an MAA before the PIP is finalized, the application will be deemed invalid or rejected. Therefore, the PIP timeline must be mapped against the MAA timeline with extreme precision.

Paediatric Use Marketing Authorisation (PUMA)

For products that are off-patent and intended exclusively for paediatric use, there is an alternative pathway: the Paediatric Use Marketing Authorisation (PUMA). The PUMA provides 8 years of data protection (compared to the standard 10 for new active substances, but with a different calculation method that often results in effective market exclusivity similar to new products). The PUMA pathway is designed to incentivise the development of paediatric formulations of older drugs.

For teams working with established products, the PUMA pathway requires a PIP just like a new active substance. However, the development program is often simpler as the safety profile in adults is well-known. The strategic question for developers is whether to pursue a PUMA or to extend an existing patent-protected product into the paediatric space. The PIP requirement applies in both scenarios, but the regulatory scrutiny on the clinical data requirements may differ.

Comparative European Context and National Nuances

While the PIP regulation is harmonised EU law, its practical application can have nuances across Member States, particularly regarding the timing of national paediatric approvals and the interpretation of the PIP results.

Germany and France: Early Engagers

Germany (BfArM) and France (ANSM) are known for their rigorous assessment of paediatric data. National competent authorities (NCAs) often scrutinise the PIP results closely during the national phase of the MAA assessment. In Germany, the AMNOG (Act on the Reform of the Market for Medicinal Products) process evaluates the added benefit of a new drug. If the drug has a PIP, the paediatric data generated (even if deferred) will eventually feed into the benefit assessment. Teams must ensure that the PIP is designed not just to satisfy the EMA, but to generate data that will be accepted by NCAs for reimbursement and pricing negotiations.

Scandinavian Approaches

Scandinavian countries (e.g., Sweden, Denmark) have strong ethical frameworks for paediatric research. While they adhere to the EU regulation, their national ethics committees may impose additional requirements regarding consent procedures or the inclusion of children in clinical trials. Developers planning clinical sites in these regions must factor in these local requirements, which may extend the timeline for site initiation and patient recruitment.

The UK Post-Brexit Context

Since Brexit, the UK (MHRA) operates a separate system. The UK has adopted the EU PIP regulation into UK law, but the MHRA does not have a direct equivalent to the PDCO. Instead, the MHRA assesses PIPs as part of the MAA. This creates a divergence. A product approved in the EU with a PIP does not automatically have a paediatric authorisation in the UK. Developers must submit a Paediatric Investigation Plan to the MHRA separately. This dual-track requirement is a common source of delay for teams treating the UK as an afterthought to the EU process.

Practical Implementation for Development Teams

To avoid the pitfalls that lead to delays, development teams must operationalise the PIP requirement from the very beginning of the drug discovery phase.

Preclinical Considerations

The PDCO often requires juvenile animal studies if the drug acts on systems undergoing development (e.g., CNS, skeletal). These studies must be planned and executed early, as they take time. Waiting until the adult Phase III is complete to start juvenile toxicology is a recipe for a delayed PIP submission. The PIP strategy must include a plan for these non-clinical studies.

Formulation Strategy

Paediatric patients cannot always swallow adult tablets. The PIP must address the development of age-appropriate formulations (liquids, dispersible tablets, patches). This is a pharmaceutical development challenge that requires significant lead time. The PDCO will expect a timeline for the availability of these formulations. If the formulation is delayed, the PIP is delayed, and the MAA is delayed.

Data Sharing and Transparency

The regulation encourages the use of existing data to avoid unnecessary testing in children. The EMA maintains a database of PIPs and waivers. Teams should actively search this database before designing their PIP. If a competitor has already conducted a specific study in a specific age group, it may be possible to argue for a waiver based on the availability of that data, provided it can be accessed and utilised (e.g., through data sharing agreements or literature).

Resource Allocation

Managing a PIP requires dedicated regulatory and clinical resources. It is not a task for a generalist regulatory manager. Teams need a PIP specialist who understands the specific language and expectations of the PDCO. The cost of a PIP can be substantial, often running into millions of Euros for a full development program. Budgeting for this early is essential to avoid programme stalls due to lack of funds later in development.

Conclusion: The PIP as a Strategic Asset

The Paediatric Investigation Plan is often viewed as a regulatory hurdle, a bureaucratic box to tick. However, a well-designed PIP is a strategic asset. It forces the developer to think about the long-term lifecycle of the product, including its use in vulnerable populations. By engaging early with the PDCO, securing appropriate waivers or deferrals, and aligning the PIP timeline with the overall development strategy, teams can transform a potential bottleneck into a streamlined pathway for market access. The key is to respect the rigidity of the EU framework and to prepare the scientific and administrative groundwork long before the MAA is even contemplated.