Paediatric Investigation Plan (PIP): 10 Steps to a Successful Application

Paediatric drug development often does not mirror the development of drugs for adults. Clinical trials in the paediatric population (0 to <18 years of age in the EU) can be more demanding than those in adults. Therefore, proper and advanced planning of the EU PIP strategy for the application, together with a transparent and justified written scientific document are key. A well-written, fully comprehensive PIP application will avoid long delays to clinical development pipelines.

Here are 10 tips for a streamlined and successful initial PIP application:

1. Planning

PIP application preparation and drafting can sometimes take up to 7 months in total (3 months preparation, 4 months of PIP application drafting). The Applicant must have a clear strategy before initiating drafting, however, this is not often the case, and changes to the strategy usually arises from the drafting of the PIP scientific document. The EMA scheduled PIP submission deadlines can help to make a plan.

2. Check the EMA website on PIP opinions

These set a precedent on the strategy of the PIP where the Paediatric Committee (PDCO) has already reviewed an application with a similar product or concerning a similar condition/indication. This is a good starting place to see, for example, what waivers, if any, were accepted by the PDCO.

3. Condition vs. indication

The PIP scientific document (Part B) requires an in-depth description of the condition in all paediatric subsets (backed by epidemiological evidence), upon which the indication (in adults and children) is based, and if it doesn’t exist, this should be stated too, and a waiver considered. Be aware that one or more (therapeutic) indications in different populations may be covered by the same condition. For example, breast cancer exists in adolescents (12 to <18 years) and adults, but metastatic, HER2-positive breast cancer only affects female adults. Distinguishing the difference between the condition and the indication can often be confusing for the Applicant, but it is important since the PDCO always considers any unmet medical need in paediatrics and therefore there is the potential that the PDCO can request a broader indication than the one proposed, or one not pursued in adults. An EMA/PDCO policy defining conditions vs. indications explains this in more detail.

Completion of this section can often help to identify the need for a waiver and subsets of the paediatric population that would be most appropriate for studying.

4. Waiver

Justifying a waiver for a particular age subset is paramount (Part C of the PIP scientific document). A lot of PIPs propose under-justified waivers, particularly in very young paediatric subsets. Waivers must be defended based on the lack of efficacy/safety, lack of significant therapeutic benefit or the disease/condition not occurring in the specific (or all) age group(s). It is not sufficient to simply state that a disorder is rare in children, and therefore studies are not feasible, to obtain a waiver. In such cases, a prevalence analysis should be carried out, supported by available data from the literature, expert opinion, patient registries, real life data repositories, paediatric research networks or initiatives. Furthermore, “alternative” arguments for waiver requests, such as, the study will be difficult to conduct, are not acceptable by the PDCO.

5. The proposed paediatric development in the chosen paediatric age group not covered by a waiver

This requires an agreed overall strategy for the quality, non-clinical and clinical development (Part D of the PIP scientific document). For proposed clinical studies, a basic protocol or synopses level of detail is required. For this section of the scientific document, it important to consider the following aspects of paediatric drug development in relation to data already generated on the drug product:

• Need and development of an age-appropriate formulation (this must cover the whole paediatric group covered by the PIP).
• Need and design of juvenile animal studies (unless already conducted or not required in accordance with guidelines).
• Design of age-appropriate clinical studies, especially, sample size/power analysis, clinically relevant and validated endpoints, inclusion/exclusion criteria, dose, duration of treatment and long-term follow-up. The EMA have published recommendations for discussions about clinical trial preparedness in paediatrics.

6. Novel therapies and orphan drugs

Writing becomes more challenging, the more novel a therapy is and whether it is an orphan drug product, as traditionally the PDCO expects a full clinical development plan up to phase 3 studies to be included within the PIP. With this in mind, the EMA recently (February 2023) launched a pilot ‘stepwise PIP’ (sPIP) programme when there is a lack of crucial information needed to decide on certain parts of the PIP, such as whether a clinical study for a whole age group is necessary. The sPIP concept will allow, in selected cases, to leave some elements of a PIP open to further refinement after first agreement, with a commitment to fill the gaps once certain measures are reached and/or new scientific data becomes available.

7. Timelines

Don’t forget to include timelines and dates for proposed measures which should be reasonable and not extended without good rationale (Part E of the PIP scientific document). These are binding, meaning that after agreement on the PIP has been obtained, they may only be changed via a PIP amendment.

8. Deferrals

The application for deferral(s) of a study or studies that are initiated or deferred in relation to the submission date for the MAA is product-specific and is generally driven by practical considerations. It is often the case that a paediatric development extends beyond the adult clinical development plan and is completed after the MAA with adult data. A deferred study must include a proposed completion date and should be justified.

9. Key elements form

This separate PDF form should include the details of all ongoing and proposed paediatric development plans as discussed in Part D (quality, non-clinical and clinical studies). These are also known as measures and should also include deferred studies. It is best to leave completion of this binding document to the end, once the protocol strategy has been developed.

10. Regulatory guidance, scientific guidelines, scientific advice

By following the EU guidance on the format and content of PIP applications, validation queries and delays to potentially life-saving paediatric medicines will be avoided. Also consider making use of the abundant list of scientific guidelines dedicated to pharmaceutical development in paediatrics, published by EMA. Furthermore, be aware that previous scientific advice between the Applicant and EMA is binding to the PIP and any deviations should be duly justified.

Summary

A Paediatric Investigation Plan (PIP) is a research and development requirement aimed at ensuring the availability and conformity of medicines to the paediatric population in all disease conditions and that has been considered and agreed by the PDCO. It is essential to have one approved in order to submit an MAA in a new molecular entity or one covered by a patent and, therefore, is extremely important.

The PIP application should contain a solid scientific basis to justify all requests within the application, whether it be a waiver, deferral or the clinical protocol development, and for all paediatric subsets. It is no easy feat! Yet, it is important to keep in mind that the PIP is a plan and thus may be subject to subsequent change via a modification procedure, as more evidence becomes available.

DLRC can support you with the complete PIP journey from the application process and up to final compliance. To find out how we can help you contact our experts using the link below or email us at hello@dlrcgroup.com.