Potential for future change to Paediatric Investigation Plan (PIP) waivers following the introduction of the new Pharmaceutical Regulations.
Current legislation; PIP background and waivers
In recognition of the need to consider children in the development of medicinal products, the European paediatric regulations (Regulation (EC) No 1901/2006 and No 1902/2006) came in into force in 2007. These regulations introduced the need for a PIP to be agreed with the Paediatric Committee (PDCO) at the EMA early in development of a medicinal product, ideally following completion of adult pharmacokinetic studies (most often during Phase 2). Compliance with the agreed PIP is required as part of Marketing Authorisation Application (MAA) for any new medicinal product, with certain MAA exempts such as generics.
The PIP ‘measures’ set out the clinical, nonclinical, quality and modelling and simulation studies required to generate the data to support a paediatric indication in the condition for which the molecule is being developed. The timing of each measure is defined within the PIP, with the start and completion of the paediatric studies either before MAA for the adult indication or deferred to after MAA for the adult indication. PIP measures are deferred if it is important to establish safety and efficacy in adults before children or if paediatric studies are likely to take longer than studies in adults. The timings of the PIP measures are more complex should the development plan include children (participants under 18 years) within the initial pivotal Phase 3 studies.
The PIP must include all relevant paediatric subsets, however, appropriate agreed waivers can be granted by the PDCO. Class waivers are accepted for medicinal products treating or preventing a condition that does not occur in children (e.g., Alzheimer’s) or for medicinal products with similar pharmacology to medicines already shown not to be effective in children (e.g., Her-/epidermal growth factor-receptor antibody medicinal products). Class waivers are defined in the EMA decision CW/0001/2015. Product specific waivers are possible if justified on grounds of safety, or where the product is not expected to represent a significant therapeutic benefit for either all paediatric subsets, or for one or more paediatric subset only, in a particular condition. In the case of full PIP waivers, the Sponsor would be able to perform clinical studies in adults to support a MAA for an adult indication only without the requirement to conduct trials in children.
New Pharmaceutical Regulation; Mechanism of action PIP for waiver applications
The proposed regulatory framework of the new Pharmaceutical Regulations (Article 75) will allow the EMA to require the Sponsor to agree to a Mechanism of Action (MoA) PIP when a PIP waiver is sought for conditions that do not occur in children. This means that, should an investigative medicinal product be developed for a disease that does not occur in the paediatric population, paediatric studies may be mandated by EMA for a different disease or condition in the same therapeutic area based on the MoA of the medicine (i.e., the medicinal product targets molecular moieties relevant to the paediatric population). This will encourage development in the paediatric population independent of the adult population and will ensure that promising therapeutic options are adequately investigated regardless of the primary MAA indication.
The new Pharmaceutical Regulation will align the EU with the US, where the Research to Accelerate Cures and Equity (RACE) for Children Act of 2017 was implemented in 2020. This Act mandated oncology MOA-based initial pediatric study plans (iPSPs), given that cancers in children are often different to those in adults. The new EU Regulation has a wider application compared to the US Act, as it will apply to medicines targeting indications within both oncology and non-oncology.
MoA PIPs would only be put in place if supported by existing scientific data, however, the expectation and methods for the generation of robust scientific data needs to be defined. The Nonclinical Working Party at the EMA is currently drafting a concept paper on ‘Proof-of-concept data supporting the development of anti-cancer products in paediatric patients’, which should be available for public consultation in 2026. This should help inform the regulatory framework for MoA PIPs in paediatric oncology, however, detailed EMA interpretation and guidance of the Article 75 waiver requirements would be needed to inform Sponsors and ensure robust workable development plans. The introduction of a molecular target list with paediatric relevance by regulators would aid Sponsors developing medicinal products. The revision of the current EMA waiver lists would be needed in order to remove the diseases and conditions that occur only in adults, where the product’s or class mechanism of action may target pathology in another disease or condition that does occur in children.
Conducting clinical trials in children in a particular disease before adults has risks and may not be feasible if the uncertainty around these risks are unacceptable to Investigators and parents and lead to poor study recruitment. It will be important to prioritise paediatric clinical trials where there is an unmet need that confer the most benefit to children. However Sponsors will need to thoughtfully consider their paediatric strategy to ensure that waivers can be adequately justified and consider the business implications of needing a MoA based development plan.
How can S-cubed help you?
S-cubed are able to support clients in obtaining and maintaining a PIP from authoring of the scientific documentation, preparation and submission of the application through to responses to the EMA’s PDCO questions and determination of the outcome.
Any Questions?
If you have any questions on this topic, please don’t hesitate to ask. You can contact us here, via email (info@s-cubed.co.uk), and telephone (S-cubed Ltd: +44 1235 77 22 60).