EU Paediatric Investigation Plan preparation and submission: your strategy for success

What is a paediatric investigation plan?

An EU Paediatric Investigation Plan (PIP) is a development plan that supports the authorisation of safe, effective and high-quality medicines for children in the European Union (EU). It outlines how a medicine should be investigated in children, including study design and formulation requirements, to ensure that all the necessary data is obtained and medicines are appropriately tested for paediatric use.

Understanding the intricacy of this regulatory framework is key as your EU marketing authorisation application must include the results of any tests outlined in an agreed PIP, unless you obtain a deferral or waiver. Additionally, the results of these tests must also be included if you’re looking to address a new indication or introduce a new pharmaceutical form or route of administration for a medicine that already has marketing authorisation.

Successful completion of a PIP also offers a number of benefits. This includes a six-month patent extension, two years of additional market exclusivity for orphan drugs, and free scientific advice from the EMA on paediatric questions.

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Preparing a PIP

Regulations state that applications should be submitted ‘not later than upon completion of human pharmacokinetic (PK) studies’, and justification is needed if the PIP is going to be submitted late. What this means practically is that you need to submit your PIP to the EMA at the beginning of the development process and incorporate PIP planning into your development strategy early on. This allows your team to integrate paediatric development into overall plans, gives you enough time to develop age-appropriate formulations, helps identify any challenges you might face early in the process, and allows you to allocate the resources and time you’ll need to complete the process.

If you’re planning a PIP, you’ll need to set aside 9-10 months from submission to decision, with additional time needed for preparation. As EU regulations are highly detailed and specific, with strict timelines and procedures, many smaller developers or those new to the EU regulatory landscape can find PIP processes a drain on time, teams and budgets.

Working with a regulatory strategy consultant, like MWB Consulting, in these early stages of the PIP process can help you plan more strategically and optimise timelines, identify unexpected challenges or find gaps in your data to further reduce risk. For example, we can determine what product-specific waivers or deferrals are available and if they are likely to be accepted, and whether a clinical or PK study is needed. We can work alongside your existing team to help plan resource or offer advice, or you can outsource the work entirely to us, freeing up your teams to concentrate on core projects.

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Submitting a PIP

You’ll need to submit your PIP via the EMA’s IRIS platform and you should include:

• An overview of the condition and medicine
• Detailed product quality specification, including the development of an age-appropriate formulation
• Plans for proposed non-clinical studies and clinical study plans for each age group
• Measures to monitor safety and efficacy
• A timeline for the completion of studies

Once you’ve submitted your PIP, it’s validated by the EMA, and the Paediatric Committee (PDCO) makes an initial assessment. If they have questions, they’ll then send these to you. You have the opportunity to address these questions, modify your original proposal and prepare updated documentation (if applicable). Your responses are reviewed by the PDCO and they discuss any outstanding issues before drafting and adopting an opinion. Based on this opinion, the EMA issues a decision.

The PDCO can give:

• Full PIP approval
• Partial waiver (for certain age groups)
• Full waiver (if medicine is unlikely to benefit children)
• Deferral (allowing adult studies to be completed first)

During your submission, regulatory strategy consulting firms can also provide valuable help, advice and insights to reduce the risk of costly mistakes and delays and maximise the chances of first-time approval.

At MWB Consulting, we can:

• Act as your liaison with the EMA and PDCO
• Submit your application correctly and by the agreed deadline
• Write your full PIP submission or offer an expert review of your documentation
• Draft optimal question responses for the PDCO and successfully defend your submission
• Prepare your team for, or represent you in, face-to-face meetings
• Interpret feedback received from the PDCO
• Reassess your submission strategy, if needed
• Help you get an agreed PIP that can later be modified as new data or considerations become relevant.

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What happens after a PIP submission?

Following a successful PIP submission, you can move on to the implementation phase, beginning paediatric studies to the agreed timelines. However, there are also ongoing requirements to consider. These include annual reports to the EMA on study progress, compliance with agreed timeliness, and maintenance of study quality standards. In time, you’ll also need to submit your study results to the EMA and prepare final reports. 

These ongoing requirements mean that demands on your resource, time and budgets don’t end with a successful approval. That’s why MWB Consulting can work with you on an ongoing basis, offering guidance on long-term compliance and progress reporting. We also stay updated with regulatory changes to help you incorporate future developments into your plans.

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How does the UK PIP process differ from the EU?

Since Brexit, the UK has had its own PIP process, which is similar to that in the EU. If you’re looking to develop medicines in both the UK and EU, you’ll now need to navigate both systems, although alignment has been maintained where possible.

Key differences include:

• Different submission timelines
• UK-specific requirements and contact points
• A separate review process
• UK-specific market protections

You must submit UK Paediatric Investigation Plans (UK-PIPs) via the Medicines and Healthcare products Regulatory Agency (MHRA) portal and all information must be relevant specifically to the UK. This applies particularly to any areas of unmet therapeutic need the drug in development is intended to cover. You’ll also need to submit additional administrative information (which acts as a letter of intent) via the portal two months before the actual submission.

To add further complication, UK-PIP submission requirements vary depending on the status of the PIP in the EU:

• EU-PIPs, modifications and full product specific waivers with an EMA decision agreed before the 1st of January 2021 will be adopted as UK-PIPs and do not require re-submission to the MHRA.
• Where a valid request for an EU-PIP, modification or waiver has been made to the EMA but the decision was given after the 1st of January 2021, the EU-PIP will be adopted as a UK-PIP if the PDCO gave a positive opinion before the 1st of January 2021 and there is no requirement to re-submit to the MHRA.
• If the PDCO gave a negative opinion before the 1st of January 2021, it will be considered a refused submission. Developers can re-submit an updated PIP to the MHRA, outlining how they have addressed the refusal reasons.
• If the PDCO gave a positive opinion after the 1st of January 2021 or there is an ongoing EMA assessment, and there is a delay to the UK-PIP submission, the MHRA will aim to maintain alignment with the PDCO opinion if one is reached before the MHRA assessment is completed. However, divergence could occur as decisions will be made based on UK public health needs.
• If there is no EU-PIP submission before the 1st of January 2021 or the PDCO gave a negative opinion after this date, a full UK-PIP submission is required. If there has been a negative opinion, developers should outline this and demonstrate how they have updated their submission in response.

All UK-PIP submissions should outline any agreed EU-PIP agreements of opinions, any ongoing EU-PIP assessments and the timelines, and any current scientific divergence between the UK-PIP and EU-PIP. Full supporting documentation is required in all cases.

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A strategy for success

Whether it’s in the EU or UK, preparing for and submitting a PIP is a complex and involved process that can take more than twelve months. We recommend starting early with a comprehensive strategy to give yourself the best chance of success. It’s also important to closely adhere to the defined process, regularly monitor study progress, submit any modifications in good time and prepare all documentation carefully. We also advise making use of any help that the EMA or MHRA offers and taking time to hone any communication you have with regulatory bodies.

Partnering with a regulatory strategy consulting firm, like MWB Consulting, can help you navigate the complex regulatory landscape in the EU and UK. Our services may prove particularly valuable if you’re a smaller developer without a large budget, you’re new to these regions or you don’t have an internal regulatory team. We can work with you for part, or all, of your PIP submission to help you reduce risk, save time and money, and increase your chances of a successful outcome.