Stepwise Paediatric Investigation Plan — Evolutionary or Revolutionary?

A New Initiative of the European Medicines Agency to Support Paediatric Medicines’ Development. 

HsinYi van Eekelen, Senior Clinical Strategy Scientist, and Richard Veselý, VP Regulatory Strategy  

Introduction  

At the time of the Paediatric Regulation introduction in 2006 [(EC) No 1901/2006], many products administered to children were prescribed by physicians based on their off-label experience instead of targeted paediatric clinical research. The Paediatric Regulation was, therefore, implemented to reduce the level of off-label usage and its associated risks (e.g., adverse effects due to overdosing, inefficacy due to underdosing, and improper formulation for the age population) and potential delay in access to innovative medicines for paediatric-specific indications. 

The European Commission (EC) published an analysis report, The Impact of the 10 Years of EU Paediatric Regulation, in 2017. It was evident that with the Regulation in place, more children’s medicines with better information on their use by prescribers and patients are available. In addition, more ethical and high-quality paediatric research and drug development were conducted. As a result, paediatrics has become an integral part of medicine development. 

At the same time, the report also highlighted the challenges observed with implementing the Regulation. Amongst the concerns, the long duration required to complete the agreed Paediatric Investigation Plans (PIPs) contributes to the delayed access of the paediatric population. In addition, there are more challenges when developing treatments for paediatric-specific diseases and diseases that manifest differently in children than in adults. For the cases when studying rare diseases or the off-label use of other medicinal products for the same target disease is available, recruitment for paediatric clinical trials becomes even more challenging.  

Additionally, the timing of the PIP submission, which must occur no later than the completion of adult human PK studies, frequently represents a real dilemma. At this stage, the available paediatric information is understandably incomplete, and a plethora of scientific uncertainties are prevalent due to pending results from ongoing or even yet planned studies in adults. The lack of sufficient knowledge may result in ill-defined measures being included in the PIP, requiring future modifications to align with scientific advances and new evidence generated over time. Considering the scientific uncertainty and the resources needed to create the initial PIP, knowing that it will require modification, some sponsors have been tempted to delay the submission of the PIP proposal until more definitive information has been generated. However, such an approach is not only in breach of the legislation but also risks losing the scope and time to design the paediatric program optimally. It also risks making conclusions with suboptimal measures due to conflicting commitments with regulatory authorities and ethics committees of other regions. Finally, the genuine advantages of early planning for the paediatric development (the optimal use of adult data for modelling studies in children and the development of age-appropriate paediatric formulation, etc.) might be lost when “thinking paediatrics” is postponed, which does not allow adequate time to translate the scientific findings to a paediatric purpose. 

The Paediatric Committee (PDCO) of the European Medicine Agency (EMA) was struggling with accommodating these two legitimate but contradictory arguments and trying case-by-case to find an optimal solution for every application. To introduce a systematic and generally accepted way of tackling these challenges, the EC and EMA developed a detailed Action Plan on Paediatrics (the closing report February 2023).  One of the main topics in this Action Plan is to improve the handling of PIP applications, which forms the basis of the Guidance for Stepwise PIP pilot, published by EMA on 6 February 2023. 

Stepwise PIP 

The EMA proposes to pilot a non-conventional PIP approach, called stepwise PIP (sPIP), to support defining the PIP program by sponsors over time as more evidence becomes available in a scientifically sound and regulatory-compliant manner. The sPIP will consist of only a partial development program, conditional on the development of a “full,” conventional PIP once the crucial information has become available based on the agreed milestones. 

The sPIP pilot phase started in Q1 2023 with the plan to accept eight sPIP applications for the initial evaluation. The participating sponsors should contact the Paediatric Medicines (PME) Office of EMA (via Ask EMA) to explore the potential of the approach and learn more about a dedicated pre-submission meeting with the assessment team at the Paediatric Committee (PDCO). The decision of whether the sPIP approach would be applied to the envisaged paediatric program will be provided no later than the Day 30 PDCO plenary discussion. 

Requirements of an sPIP 

Not all paediatric development programs qualify for an sPIP approach. Clear scientific justifications will need to be provided to the PDCO, and a pre-submission meeting is recommended to discuss eligibility. Based on the current guidance for the sPIP, only medicinal products that have these qualifications will be considered: 

1. They are first-in-disease for the paediatric population. 
2. The mechanism of action (first-in-class) is not fully characterized. 
3. There must be multiple development options to address significant unmet paediatric needs or have several paediatric indications where adult data are lacking.  

The situations when critical PIP elements cannot be defined based on existing scientific knowledge of the study design, study population, and main objectives may also be considered for an sPIP pathway. 

The sPIP still needs to contain a minimum set of data based on state-of-the-art scientific knowledge and current drug development experience in the relevant field. The templates for the sPIP, the procedures for the sPIP, the subsequent PIP modifications, and the compliance checks will follow the same processes as the conventional PIP. 

What Does It Mean to the Sponsors? 

The sPIP provides more opportunities for the sponsors to have informed discussions with and guidance from PDCO about their paediatric programs. Pre-submission meetings are encouraged before submitting an intended sPIP and before a major PIP modification after the agreed initial sPIP. Sponsors will have a better opportunity to draft a more realistic PIP that could be easily adapted. 

Sponsors may also need to plan more time ahead of the actual (s)PIP submission as the decision on the eligibility for the sPIP pathway and the preparation and conduct of the dedicated pre-submission meeting will need more time.    

The milestones of the measures in the sPIP will focus more on the sequence of events but allow flexibility on the timing of the initiation and completion in the context of the predefined dependency of events. The rationale for these dependencies will be provided and agreed upon in the initial sPIP. For example, the timing of the milestone can be described as X months after completion of Study Y, with the aim to agree on a particular key element that would be acceptable without specifying the date in the month/year format. This would be the basis for the future PIP opinion and compliance check at the pre-authorisation stage.  

At Allucent, we have ex-Agency experts and a multidisciplinary team available to help sponsors navigate the paediatric program life cycle (including the FDA’s Paediatric Study Plan and equivalents in other geographies). We offer guidance with strategy planning, Agency interactions, the development and preparation of the PIP applications and subsequent PIP modifications, and the execution of agreed paediatric studies up to EMA partial and full compliance checks. To have a conversation about Allucent’s expertise in bringing the sPIP plan to life in your study, contact us today.