Blog Post

Successful Pediatric Investigation Plan (PIP) Application in the European Union – Part 1: Understanding the regulatory requirements

January 26, 2025

Regulation (EC) No 1901/2006 (the “Pediatric Regulation”), which came into effect in the European Union (EU) on 26 January 2007, introduced the obligation for Sponsors to apply for a pediatric investigation plan (PIP) early in the drug development process and the obligation to conduct their pediatric clinical trials accordingly to a PIP agreed with the EMA. Compliance with the Pediatric Regulation is mandatory for any Sponsor seeking marketing authorization for a new medicinal product in the EU, regardless of whether the product is being developed for use only in adults or also in the pediatric population (from birth to less than 18 years of age).

More specifically, the Pediatric Regulation requires Sponsors to submit the results of the studies in the pediatric population in accordance with a PIP agreed  with the EMA’s Pediatric Committee (PDCO), or the proof of having obtained a waiver or a deferral, at the time of filing a marketing authorization application (MAA) for a new medicine, including orphan-designated products. This requirement also applies in case of significant changes (new indication, new formulation, or new route of administration) to products already authorized in the EU.

The PIP is the document that defines the overall strategy proposed for the pediatric development of a medicinal product. It specifies which subsets of the pediatric population (pre-term and term neonates, infants, children and adolescents) need to be studied, how and when. It also describes the measures to develop age-appropriate formulations or to adapt the existing adult formulation to the subsets to be studied. Ultimately, the PIP defines the clinical studies that a Sponsor plans to conduct with a specific medicinal product in the pediatric population. The PIP can contain a justified request to defer the initiation or the completion of the pediatric studies defined in the PIP until sufficient evidence of the safety and efficacy of the investigational medicinal product is available from the clinical trials in adults. However, even when requesting a deferral, the PIP must include a description of the planned pediatric studies and the estimated study timelines. The PIP needs to be agreed with the PDCO during an assessment procedure which takes on average 8 to 12 months.

In duly justified conditions where the medicinal product is likely to be unsafe or ineffective or have no therapeutic benefit to the pediatric population, or when the target disease does not affect this population, the PDCO may grant a PIP product-specific waiver which can be full or partial, depending on whether it covers the entire pediatric population or only one or more pediatric subsets, respectively. A waiver can also be granted when the target indication is listed in the PDCO´s class waiver list.

The Pediatric Regulation specifies that the PIP (or the application for a waiver or deferral) shall be submitted, unless duly justified, not later than upon completion of pharmacokinetic studies in adults, which can coincide with the initial tolerability studies, or the initiation of the adult Phase 2 studies. This requirement aims to ensure enough time for studies to be planned and conducted in the pediatric population, where appropriate, before a MAA is submitted. It also aims to ensure early dialogue with the PDCO. Sponsors may find this timing to be challenging within their still uncertain development and marketing plans, therefore some flexibility is allowed. However, where a Phase 2 study in adults is already completed by the time of the PIP submission, the submission is in principle considered delayed unless justified. Late submissions considered by the PDCO as not justified are reported in the yearly EU Commission Report. Submitting a PIP application during Phase 3 trials in adults, or after starting clinical trials in children, is considered unjustified and may pose significant risks for the Sponsor, including delays of their marketing authorization (without an agreed PIP in place or an approved waiver the MAA will not be validated in EU) and loss of the money invested in a pediatric program that does not fit the PDCO’s expectations and needs to be redesigned.

In our next blog post in this series, we will provide some key tips to help you develop a successful PIP application.

An advance of what is to come

Some pediatrics requirements will be revisited within the framework of the ongoing reform of the EU pharmaceutical legislation, which is estimated to go into effect around 2028. Some of the most relevant updates to the PIP requirements are listed below:

  • Applicable also to new strengths of authorized products.
  • An “initial PIP” followed by updates and a final PIP according to pre-defined timelines may be allowed for new active substances to treat novel pediatric conditions, on the basis of scientifically justified reasons. This initial PIP/stepwise concept is informed by the experience gathered by EMA during the pilot run in 2023.
  • Modifications of a submitted PIP may be requested by EMA during its assessment based on new information.
  • Late submissions may be subject to financial penalties.
  • A PIP may be mandatory when a waiver is requested based on the mechanism of action of the product, when targeting a molecular aspect responsible for a different disease in pediatrics within the same therapeutic area of the disease only occurring in adults.
  • Length of deferrals cannot exceed five years (extendable only in duly justified cases).

Conclusion

Successfully developing a PIP requires careful planning and a deep understanding of EMA’s regulatory requirements. The integrated team of regulatory and subject matter experts at Rho is highly experienced supporting the development of pediatric strategies, preparing PIP applications and managing the whole PIP procedure with EMA, including scientific advice and pre-submission meetings. Contact us for more information and stay tuned for our next blog post in this series where we will provide some useful considerations to assist you in developing a successful PIP application.

References

Regulation (EC) No 1901/2006 of the European Parliament and of the Council of 12 December 2006 on medicinal products for paediatric use and amending Regulation (EEC) No 1768/92, Directive 2001/20/EC, Directive 2001/83/EC and Regulation (EC) No 726/2004.

European Medicines Agency decision CW/0001/2015 of 23 July 2015 on class waivers, in accordance with Regulation (EC) No 1901/2006 of the European Parliament and of the Council.

Beatriz Criado Bueno, MSc, Director, EU Regulatory Strategy, has more than 25 years of experience in regulatory affairs in the pharmaceutical, biotech, and CRO industries where she has held a range of leadership positions in regulatory affairs. Ms. Criado is well versed in bringing products from development to market and in post-approval life cycle management regulatory activities. She has a solid background in biological and biotech-based products, and broad experience in a wide variety of therapeutic areas, including immunology, neuroscience, oncology, dermatology, rare diseases, and pediatric indications. Ms. Criado has significant experience preparing and filing regulatory submissions including more than 50 marketing applications across EEA countries and the UK and multiple orphan designations and pediatric investigation plans. She has also coordinated more than 20 CTAs including complex clinical trials such as umbrella and platform designs, more than ten Scientific Advice procedures (EMA and National) and a similar number of pre-submission meetings with EMA and National Regulatory Authorities.