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Mechanism of action in pediatric research: Regulation from FDA to EMA

Discover how EMA’s proposed MoA-based PIP requirements mirror the US RACE for Children Act and how sponsors can prepare for pediatric regulatory changes.

EMA shifts to MoA-based pediatric planning

The EU’s General Pharmaceutical Legislation is evolving. On 10 December 2025, the European Commission announced its welcome of the major reforms. Among the reform proposals is a change in the regulation to Paediatric Investigation Plan (PIP) Waivers that would require Mechanism of Action (MoA)-based PIPs. This marks a significant shift from indication-driven obligations to a model that considers pediatric relevance based on MoA.

This is similar to the FDA’s Research to Accelerate Cures and Equity (RACE) for Children Act, which aimed to ensure that cancer therapies with pediatric potential are not overlooked simply because their adult indication differs. By focusing on MoA, the EU aims to align global pediatric frameworks and increase the number of meaningful pediatric therapies, particularly in oncology, neurology and immunology.

If adopted without amendment, this requirement will reshape pediatric planning in Europe. Sponsors who stay ahead of the curve will be better positioned to comply and based on European Commission estimates, may shave 2-3 years from their pediatric clinical development programs. Success in this case will depend on assessing pediatric applicability sooner and more broadly, then creating and submitting a plan that aligns with development timelines.

What is the RACE for Children Act and why does it matter?

The concept of MoA-based obligations is not new. In the US, the RACE for Children Act introduced similar logic for pediatric oncology drug development. Passed in 2017 and implemented in August 2020, RACE requires sponsors of new adult oncology drugs to evaluate their therapies in children if the drug’s molecular target is relevant to pediatric cancers even if the adult indication does not occur in children. Consider drugs developed for adult solid tumours such as lung or thyroid cancers that harbour NTRK gene fusions. These fusions are also found in several pediatric cancers, including infantile fibrosarcoma and certain pediatric sarcomas—and under RACE for Children and the potential EMA regulation this would trigger the obligation to submit a pediatric study plan and conduct relevant trials despite being different indications.

This was a major shift from previous rules under the Pediatric Research Equity Act (PREA)i, which allowed exemptions for orphan drugs and focused on adult indications. By closing the orphan drug exemption and prioritising molecular targets, the RACE for Children Act significantly increased the number of potential drugs for pediatric consideration. Early data show that in the first year of implementation, nearly 43% of newly approved oncology drugs were required to conduct pediatric studies, compared with just 8% before the RACE Act took effect.ii

Therapeutic areas expected to benefit most from this approach include pediatric oncology, neonatology and neurodegenerative diseases. These fields often share molecular pathways with adult conditions, making MoA-driven planning particularly impactful.

Challenges of MoA-based PIPs: What sponsors need to know

While promising, MoA-based requirements introduce complexity. Mapping mechanisms to pediatric conditions is challenging, especially in oncology, immunology and rare genetic diseases, because the same molecular pathway can behave differently across age groups and disease contexts, making relevance and safety harder to predict. Timing and strategy become critical, as pediatric planning must align with adult development to avoid delays.

Waivers will also evolve. Consider Alzheimer’s disease (AD): drugs targeting amyloid beta (Aβ) pathology may be excluded by indication but included by MoA because Aβ is implicated in other neurological conditions such as Down syndrome, Autism Spectrum Disorder and Fragile X syndrome.

While mapping adult condition MoAs to pediatric populations can be challenging and requires concerted strategy, the industry does have strong starting points. The Paediatric Committee (PDCO) references multiple opportunities where MoA may warrant the development of pediatric medicine. However, despite knowing there are potential pathways to pediatric therapies in certain disease areas, PDCO cannot at present enforce the requirement beyond strongly worded letters. 

Connecting the dots: How ICON helps sponsors with MoA-based pediatric planning

ICON’s Centre for Pediatric Clinical Development brings deep expertise to this space, with experience on more than 420 pediatric studies in the past five years across multiple therapeutic areas. This experience allows ICON to connect the dots between complex mechanisms, regulatory expectations and clinical feasibility, ensuring PIPs are not only compliant but also practical and scientifically robust. 

Our integrated approach ensures all the cross-functional expertise and momentum are fully harnessed. We embed pediatric strategy early in development, helping sponsors avoid delays and maximise regulatory alignment. 

Our scientific and clinical teams identify pediatric relevance across MoAs, even in complex or emerging areas. ICON’s PIP service leverages cross-functional expertise—from pharmacologists to regulatory specialists to therapeutic expertise—ensuring PIPs are thorough and practical. The result is custom designed comprehensive plans that navigate the evolving therapeutic and regulatory landscape. Where relevant, we can help shape development strategies to incorporate MoA-style PIPs effectively.

Regulatory strategy: Avoiding delays and managing PDCO engagement

Developing a compliant PIP is only part of the challenge. Negotiating with PDCO adds another layer, and questions remain about oversight as the framework evolves. ICON Regulatory Affairs brings extensive experience in PIP submissions, including deferrals and waivers, and stakeholder engagement. We prepare sponsors for PDCO interactions and help manage feedback to reduce risk and improve outcomes.

Managing uncertainty: Staying ahead of evolving EMA guidance

Like the RACE for Children Act, the proposed MoA PIP requirement signals a broader regulatory shift toward pediatric inclusion. While advantageous to patient populations in the long run, it may also create opportunities for sponsors. Pursuing a similar PIP in Europe could unlock incentives such as the Supplementary Protection Certificate (SPC), extending market exclusivity and improving return on investment.

However, the MoA PIP framework is still developing. Grey areas remain around scope, timing and applicability. Questions arise around which mechanisms qualify, how early sponsors must commit, and whether waivers will apply in borderline cases. These uncertainties make proactive planning and project management essential.

ICON maintains line of sight with regulators and industry bodies to anticipate changes and interpret evolving guidance. Our teams help sponsors adapt strategies as requirements crystallise, ensuring compliance without compromising development timelines. By combining regulatory insight, scientific expertise and operational infrastructure, ICON provides clarity where the rules are still in flux, reducing risk and positioning sponsors to benefit from incentives while meeting pediatric obligations.


Engage ICON early to stay ahead of the curve and ensure your pediatric strategy is inclusive, feasible and scientifically sound. Connect with our experts today. 

 

References

[i] United States Congress. Pediatric Research Equity Act of 2003, Pub L No. 108-155, 117 Stat 1936 (2003). Available at: https://www.congress.gov/108/plaws/publ155/PLAW-108publ155.pdf

[ii] American Association for Cancer Research. RACE Act Increased the Number of Cancer Drugs with Required Studies for Use in Pediatric Patients. Published April 11, 2022. Accessed December 2, 2025. https://www.aacr.org/about-the-aacr/newsroom/news-releases/race-act-increased-the-number-of-cancer-drugs-with-required-studies-for-use-in-pediatric-patients/

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