1. Overview

This guidance explains the process for applicants applying for a paediatric investigation plan (PIP), modification, waiver or compliance check. It explains UK paediatric requirements including those related to applications made through the International Recognition Procedure (IRP) and includes changes related to the Windsor Framework arrangements for medicines, which come into force on 1 January 2025.

You should read this guidance in conjunction with the guidance on the format and content of paediatric investigation plans and related applications in the UK. The format and content guidance provides definitions of terminology used in this guidance.

2. General approach to UK paediatric investigation plans

The legal requirements for United Kingdom (UK) paediatric medicines are set out in the Human Medicines Regulations 2012 (HMRs), as amended.

This guidance addresses the common scenarios for paediatric submissions to the MHRA. A case-by-case discussion should always be considered for paediatric submissions that do not meet the criteria listed in this guidance.

All MHRA regulatory submissions which trigger the UK’s paediatric requirements must have an agreed or adopted UK PIP (and relevant compliance checks) or full product specific waiver or confirmation of a class waiver in place. This applies irrespective of regulatory route (direct national, IRP, Access or Project Orbis).

Applicants must include the latest MHRA decision documents (and MHRA compliance check outcomes, if applicable) in the MHRA regulatory submission which triggers paediatric requirements to ensure validation of the marketing authorisation (MA) or variation application.

Agreed paediatric plans from other regulatory authorities cannot be used to validate an MHRA regulatory application. This is regardless of whether a paediatric study/investigation plan has been agreed by another regulator in the context of an IRP, Access or Project Orbis application.

All requests for agreements of UK PIPs, full product specific waivers, confirmation of class waivers, modifications and compliance checks for agreed or adopted UK PIPs must be submitted to the MHRA through the dedicated PIP submissions portal.

Further information on the format and submission process for PIPs and related procedures via the MHRA submissions portal is available in separate, published user reference guides in the portal and via published guidance. Email applications for these procedures will not be accepted.

Applicants should include information that is relevant and specific to the UK, particularly with respect to any areas of unmet therapeutic need that the product intends to cover (see section 8).

EU PIPs which became UK PIPs on 1 January 2021 will be referred to as adopted UK PIPs in this guidance.

New PIP submissions after 1 January 2021 that have been assessed and agreed by the MHRA will be referred to as agreed UK PIPs in this guidance.

3. The Windsor Framework

Until 31 December 2024

Where applicable, UK paediatric requirements apply to Great Britain-only MA applications and variations, whereas UK and EU paediatric requirements apply to UK-wide MA applications and variations.

After 1 January 2025

The MHRA will license medicines across the whole of the UK from 1 January 2025.

Medicines that were previously within the scope of the EU’s centralised procedure will be authorised under UK-wide MAs and no longer be limited in territorial scope as GB MAs. These products will be designated in line with definitions in UK law as ‘category 1’. Medicines outside this scope (which can already be authorised as UK-wide MAs), will be designated as ‘category 2’. Each MA application and existing authorised product will be assigned by the MHRA to one or other category.

Where applicable, UK paediatric requirements will apply to MA applications and variations for category 1 products whereas UK and EU paediatric requirements will continue to apply to MA applications and variations for category 2 products. Detailed information on UK-wide licensing and product categorisation is available in the UK-wide licensing of human medicines guidance.

The MHRA expects that the majority of regulatory submissions triggering paediatric requirements will be for category 1 products. Guidance on specific paediatric requirements for category 2 products is provided in section 9.

4. PIP submissions

4.1 Applications subject to paediatric requirements

Since 1 January 2021, the requirement for certain applications to include the results of a PIP are set out in Regulation 50A of the HMRs.

The following MHRA regulatory applications are subject to PIP requirements, regardless of route (direct national, IRP, Access or Project Orbis).

Initial marketing authorisation applications:

Regulation 50: new active substance, or
Regulation 50: known active substance, or
Regulation 55: fixed combination products, or
Regulation 50E: paediatric use marketing authorisation applications (PUMAs)

Line extensions (changes to the active substance(s) including the salt/ester, isomer or biological active substance, or changes to strength, pharmaceutical form or route of administration):

where a supplementary protection certificate (SPC) or a qualifying patent applies, and
application is for new indications, new pharmaceutical forms or new routes of administration

Variations:

to add new indications where an SPC or a qualifying patent applies
related to PIP implementation

4.2 Timing of UK PIP submissions

According to Regulation 50B (3) of the HMRs, applications for the agreement of a PIP should be submitted, unless duly justified, ‘not later than upon completion of the human pharmaco-kinetic (PK) studies’, as specified in section 5.2.3 of Part I of Annex I to the 2001 Directive,’ unless the MHRA agrees to accept a later request.

In general, paediatric investigation plans should be submitted early during product development, in time for studies to be conducted in the paediatric population, and before marketing authorisation applications are submitted.

The timing of submission should not be later than the end of healthy subject or patient PK, or if PK studies are not relevant, at the initiation of the adult phase-II studies (proof-of-concept studies). Submitting a PIP application for a new active substance during confirmatory or phase-III trials in adults, or after starting clinical trials in children, is likely to be considered unjustified.

Submission of PIPs to the MHRA in parallel to other regulators is strongly supported to allow robust parallel assessment and alignment of the agreed paediatric plans across jurisdictions.

4.3 Paediatric plans agreed with other regulators

If paediatric requirements are triggered in any other regulatory jurisdiction, the latest PIP/paediatric plan, product-specific waiver opinion/decision or class waiver opinion/decision should be submitted as part of the UK-PIP application via the MHRA PIP submission portal.

The PIP application cover letter should include information about paediatric plans that have been agreed with other regulators. The agreed paediatric plan(s) should be submitted if available. The cover letter should also include information about any ongoing paediatric plan assessment by other regulators, and its timeline in the assessment cycle (for example day 30, 60, clock stop, day 90 or 120 for EU PIPs).

The MHRA will consider the agreed paediatric plan in its approach to assessing the UK-PIP or waiver (see section 4.4).

If the applicant chooses to submit a PIP to the MHRA which has a negative outcome from another regulator, the applicant should declare this outcome and incorporate into the UK-PIP the recommendations to resolve those aspects which led to the negative assessment.

Guidance on specific paediatric requirements for category 2 products is provided in section 9.

4.3.1 UK-PIP submission with an agreed EU PIP available

A UK-PIP submission is required, in alignment with the MHRA’s guidance on the required format and content of applications for agreement or modification of a PIP.

Applicants are encouraged to submit the agreed EU PIP and relevant documents as part of the UK PIP submission. Applicants should submit:

any scientific divergence between the submitted PIP application and the agreed EU PIP, briefly summarised in the cover letter
the agreed EU PIP, paediatric committee (PDCO) opinion or EMA decision and supporting documentation

When assessing the UK-PIP, the MHRA will consider the EMA Decision/PDCO opinion on the EU-PIP, bearing in mind that the UK assessment will be based on the UK’s paediatric public health requirements and criteria listed in section 4.4 below.

4.3.2 UK-PIP submission with only a non-EU paediatric plan available

A UK-PIP submission is required, in alignment with the MHRA guidance on the required format and content of UK PIP applications.

As part of the UK PIP submission, applicants are encouraged to submit the agreed non-EU paediatric plan decision and relevant supporting documents.

When assessing the UK PIP, the MHRA will consider the measures agreed in the paediatric plan.

4.3.3 Standalone UK PIP submission

This section applies if there is no corresponding agreed EU PIP submission, and no relevant paediatric plans agreed with other regulators.

The MHRA will carry out a full assessment of the PIP application.

The applicant should additionally clarify in the cover letter if:

there has been a previous negative paediatric plan outcome (such as a negative EMA decision / PDCO PIP opinion)
there was a withdrawn paediatric plan application (such as an EU-PIP prior to the adoption of an EMA decision /PDCO opinion)
the current UK submission addresses the comments of the other regulator on the negative or withdrawn paediatric plan
the previously withdrawn or negative paediatric plan and/or summary report (SR) has been provided as part of the supporting documents in the MHRA submission

During assessment, consideration will be given to the scientific discussions of the other regulatory agency, which led to the negative opinion or the withdrawal of the paediatric plan.

4.4 Assessment criteria for UK PIPs

UK PIP assessment must consider national paediatric public health needs by considering (but not restricted to) the following criteria:

unmet UK paediatric needs (section 8 of this guidance)
paediatric only development particularly for an innovative product (such as a new drug class)
tumour or condition agnostic development related to a product’s mechanism of action
the incidence of the disease in the UK population
any additional safety or efficacy concerns for the UK population
the nature and number of licensed products already available for the intended paediatric indication
the feasibility of performing the proposed paediatric studies in the UK only
PIP is to support a UK paediatric use marketing authorisation (PUMA)
neonatal only development
urgent/emergency public health need

Therefore, divergence could occur between the agreed UK-PIP and agreed paediatric plan from another regulator.

4.5 EU PIPs, modifications to PIPs and full product specific waivers with EMA decisions / PDCO opinions completed before 1 January 2021

The EMA decision/ PDCO opinion has been adopted as the UK outcome for:

EU PIPs, modifications and full product specific waivers with an EMA decision before 1 January 2021
EU PIPs, modifications and full product specific waivers where the EMA paediatric committee (PDCO) has given a positive opinion before 1 January 2021 but there is no EMA decision

These PIP applications will not require re-submission to the MHRA unless the EU-PIP is subsequently modified.

Where a valid request for an EU PIP or modification or waiver has been made to the EMA, but the PDCO has issued a negative opinion before 1 January 2021, the MHRA will treat the EU application as refused. However, applicants can submit an updated PIP to the MHRA which addresses the reasons for refusal.

5. PIP modifications

According to Regulation 50B (6) of the HMRs, the applicant may request a modification of an agreed UK PIP if they encounter difficulties with its implementation as to render the plan unworkable or no longer appropriate. The MHRA will assess the proposed changes based on the scientific arguments provided.

All modification requests must be submitted in full via the dedicated MHRA submissions portal. Modifications must be submitted well in advance of any related MHRA regulatory submissions which trigger UK’s paediatric requirements to ensure the latest MHRA PIP decision is included for validation of the regulatory application.

Applicants can submit several modifications of the same PIP in sequence if there is prior agreement from the MHRA, and if the previous UK modification has not yet concluded. However, a negative MHRA decision on the initial modification in the sequence could likely affect the assessment of any subsequent modification submissions.

Submissions made in parallel to other regulators are strongly supported. Where an agreed EU PIP is available, further advice is provided below. The latest version of any paediatric plan agreed with a non-EU regulator should be included in the modification submission to the MHRA. A full modification assessment will be undertaken in cases where the initial UK PIP underwent full MHRA assessment.

For details on the application process, read published guidance on the required format and content of UK PIP applications.

5.1 UK PIP modification with agreed EU PIP available

In cases where the initial UK PIP was accepted based on an agreed EU PIP, the MHRA will align with a positive PDCO opinion/EMA decision where possible, following a targeted assessment of the UK modification.

Applicants who submit the UK PIP modification after the end of a corresponding EU modification procedure should do so in a timely manner to prevent undue divergence between the UK PIP and the corresponding EU PIP and delays to the relevant MHRA regulatory submissions triggering UK’s paediatric requirements.

For adopted UK PIPs which have undergone modifications in the EU since 1 January 2021, these should be submitted either to the MHRA in parallel or as soon as an EMA outcome is received, unless the applicant wishes to keep the PIPs divergent. Delayed submissions may lead to an unintended divergence between the UK PIP and the EU PIP, which may cause issues with validation of subsequent MHRA regulatory submissions and the operation of the MHRA compliance check.

Where an EU PIP is available, modification submissions should include the most recent PDCO opinion and EU PIP summary report as well as updated key binding elements. It should be confirmed in the modification cover letter if:

the modification submitted is for an adopted or agreed UK PIP
there is an agreed EU modification
a modification assessment by the EMA is ongoing
there is a significant scientific divergence between the current agreed EU PIP and the agreed UK PIP

If the PDCO opinion (or the corresponding update to the paediatric plan from a non-EU regulator) is negative while the UK assessment is ongoing:

the applicant should inform the MHRA of the outcome and confirm if they wish to withdraw the PIP modification request or continue with the MHRA assessment
once a PIP modification application has been withdrawn, a new application for a PIP modification can be submitted and will undergo review using the same assessment criteria discussed in section 4.4 of this guidance
if continuing with the MHRA assessment, the applicant can discuss amendments to the proposals before the final MHRA opinion on the proposed modification is agreed

Additional guidance on specific paediatric requirements for category 2 products is available in section 9.

6. Waivers

According to Regulation 50D (1) to (9) of the HMRs, applicants can request an exemption from the obligation to provide to the licensing authority the results of all studies performed, and details of all information collected, in compliance with an agreed paediatric investigation plan.

The MHRA regulatory applications which trigger paediatric requirements and for which full product specific waiver or class waiver may apply are the same as listed in section 4.1.

The regulatory timing of waiver submissions is also the same as for UK PIPs as listed in Section 4.2.

A UK waiver submission should follow the MHRA’s published guidance on the required format and content of these applications.

Where there is a positive PDCO opinion or EMA decision on an EU full product specific waiver or PDCO confirmation of a class waiver agreed before 1 January 2021:

these will be adopted as a UK full product waiver for category 1 and category 2 products (see section 3)
no submission to the UK is required
these EMA decision documents should be used in the MHRA regulatory submission triggering UK’s paediatric requirements, to validate the application.

6.1 Submission of paediatric class waiver

From 1 January 2025, all requests for confirmation of the class waiver must be submitted via the dedicated MHRA submissions portal using the waiver application and template request forms. From this date, email applications to ukpip@mhra.gov.uk will no longer be accepted.

The current EMA class waiver list has been adopted by the UK. Although in principle the MHRA can accept an EMA confirmation of the class waiver request, the MHRA will assess whether the class waiver applies to the product. Applicants should submit these requests following the guidance in the format and content document.

For a negative EMA opinion on whether a class waiver applies:

the applicant should submit a full product specific waiver request for the MHRA assessment, which should include negative EMA opinion on the class waiver
if there is an EMA opinion on the applicant’s subsequent product specific waiver request, then this should be made available to determine if a targeted or full assessment is required

6.2 Submission of full product specific waiver

Requests for full product specific waivers must be made via the MHRA PIP submissions portal.

Sections 4.1 to 4.5 of this guidance also apply to these applications.

Although another regulator’s waiver agreement will be considered as part of the MHRA assessment, the requirements and categories used for the agreement of waivers may differ for other regulators and may not be applicable to the UK. Therefore, these are not automatically adopted and will require assessment. A full waiver submission to the MHRA is therefore required with clear scientific justification included in the request.

7. Compliance check

According to Regulation 50A (3) of the HMRs, applicants must submit a compliance check (CC) application to the MHRA where one is required for validation of the UK regulatory submission (MA or variation application) which triggers UK’s paediatric requirements.

All MHRA regulatory submissions which trigger UK’s paediatric requirements must include the relevant MHRA CC documents if a CC is applicable. Exceptions to the provision of the MHRA CC documents are listed in Section 7.3.

Additional guidance on specific paediatric requirements for Category 2 products is available in section 9.

7.1 Timing of a compliance check submission

When considering if a measure is subject to a check for compliance in the UK, the applicant must pay particular attention to the agreed timelines of those measures which would need to be completed after the last CC and before the date of the MHRA regulatory submission which triggers UK’s paediatric requirements, to ensure compliance is met.

The request for MHRA compliance check must be submitted no later than 2 months prior to the MHRA regulatory submission which triggers paediatric requirements (see section 4.1) to ensure validation of the submission.

7.2 Compliance check procedure

All compliance checks must be submitted via the dedicated MHRA PIP submissions portal. Further guidance is available in user guides on the PIP portal and in the format and submission procedure for PIP applications to the MHRA

Before any CC submission, applicants should ensure that any modifications which could affect the compliance of the PIP, and/or validation of the regulatory application have been agreed by the MHRA.

Applicants must include as part of the CC submission an MHRA compliance check cover letter template, which is located in the MHRA PIP submission portal. This is required to confirm:

whether the UK PIP is equivalent to an agreed EU PIP
the type of regulatory application to be submitted (as per section 4.1)
the Windsor Framework category of the product (see section 3)

Additional compliance requirements for category 2 products are listed in section 9.

A full UK assessment is required for full, final or interim CC except for procedures defined in section 7.3. However, the MHRA will consider a PDCO CC outcome in the assessment if:

there is a positive PDCO CC
the UK PIP is equivalent to the EU PIP
for a partial CC, there are no additional key measures completed prior to UK regulatory submission that requires additional CC assessment

At the end of the CC procedure the applicant will receive:

an MHRA compliance report (for partial, final or full CC)
a decision letter (for final or full CC only)

These must be included in the relevant MA or variation submission, otherwise the regulatory application will not be validated.

7.3 Adopted compliance check (CC) prior to 1 January 2021

Where there is a positive PDCO partial CC prior to 1 January 2021.

this has been adopted as the UK partial CC outcome
a new MHRA compliance check submission is not required for these unless subsequent modifications have led to divergence between the UK and EU PIPs
the adopted PDCO compliance report should be submitted with the subsequent UK full or final compliance check submission

Where there is a positive PDCO full /final CC prior to 1 January 2021, and there is a PDCO opinion on compliance (that is, the PIP is considered to be completed):

this has been adopted as the UK full/ final CC outcome
a new MHRA compliance check submission is not required
the adopted PDCO opinion on compliance should be submitted with the relevant regulatory application

7.4 Non-compliance

For non-compliance due to (minor) administrative issues, or discrepancies that do not affect the scientific conduct of the study, a targeted assessment may be proposed at the time the applicant is informed of the outcome. This assessment will combine a shortened modification procedure with a rapid CC assessment.

If the above is not applicable, the applicant will be required to submit a modification for a full assessment to align the non-compliant key elements of the MHRA decision with those of the completed study report. A rapid CC can be offered at the end of a positive modification agreement.

7.5 Statements of compliance

An MHRA statement of compliance is required for any applications to the UK’s Intellectual Property Office (IPO) to claim paediatric rewards.

The full / final compliance report and decision letter issued at conclusion of the compliance check assessment is not the same as the statement of compliance for the product and cannot be used to claim relevant paediatric rewards associated with successful completion of the UK PIP.

Where appropriate, an MHRA statement of compliance will be issued with the grant letter of the relevant MA or variation application, when all of the agreed PIP measures have been completed, as follows:

the development of this product has complied with all measures in the agreed paediatric investigation plan < reference number >
the summary of product characteristics and, where applicable, the package leaflet will include the results of the studies referred to in the PIP

In cases where the expected statement of compliance has not been issued with the grant letter, the applicant/MA holder can contact RIS.NA@mhra.gov.uk to request re-issue of the grant letter. Alternatively, applicants can consider submission of a product licence variation via the Human Medicines portal, for the purpose of issuing the PIP compliance statement alone, as a Type IB (under C.I.z.).

For orphan rewards which are conferred on successful completion of a PIP, a statement of compliance will be issued for applicant records and case file. The extension of orphan exclusivity will be granted by the MHRA.

If an EU compliance statement is available, this should be included. 

8. Unmet needs in the UK paediatric population

The unmet needs for the UK paediatric population will be defined by:

therapeutic areas identified by UK health bodies as high priority public health concerns
product development in conditions identified after consultations with UK experts and patient groups
rare diseases identified under the auspices of the Department of Health and Social Care (DHSC) policy paper UK strategy for rare diseases and its associated updates
products which are intended to be authorised as orphan medicines
products that have MHRA Innovation Passport (IP) or promising innovative medicine (PIM) designations
product development as part of Project Orbis or Access Promise Pathway
product development in conditions (or paediatric groups) identified as critically important in the EMA Paediatric Regulation 10 year report

9. Specific requirements for category 2 products

Certain MA applications and variations for category 2 products will be subject to UK paediatric requirements (see sections 4.1 and 4.2), meaning that an agreed or adopted UK PIP, modification, full product specific waiver or confirmation of a class waiver must be in place. Additionally, EU paediatric requirements will apply.

For category 2 products, the procedural aspects of UK paediatric submissions for PIPs, modifications, waivers and CCs are as described in the sections above and in the guidance on format and submission procedure for PIP applications.

Cover letters for UK paediatric submissions should state clearly that the product is category 2.

Additional guidance specific to category 2 products is provided below.

9.1 PIPs and modifications

For category 2 products subject to paediatric requirements, in addition to the UK PIP, an EU-agreed PIP must be in place (unless a waiver is granted). Developers are advised to align the UK PIP and the EU PIP where possible. Reference should be made to:

section 4.3.1 (UK PIP submission with agreed EU PIP available)
4.5 (EU PIPs, modifications to PIPs and full product specific waivers with EMA decisions / PDCO opinions completed before 1 January 2021)
5.1 (UK PIP modification with agreed EU-PIP available)

Refer to the EMA website for the latest information on the submission and agreement of EU PIPs.

9.2 Waivers

The guidance provided in section 6 should be followed.

9.3 Compliance check

For category 2 products, the applicant should confirm in the compliance check cover letter that the agreed EU PIP and modifications are equivalent to the agreed UK PIP and modifications.

During the compliance check, the MHRA will confirm equivalence and issue an additional CC decision letter regarding this.

9.4 Regulatory submission of category 2 product

The following documents must be submitted with any MA or variation application that is subject to paediatric requirements:

the agreed/adopted UK PIP decision
an appended MHRA CC decision letter confirming that the agreed UK PIP and agreed EU PIP are equivalent
the relevant MHRA (or adopted) compliance check outcomes

In this case, the submission of the EU PIP decision documentation is optional.

In cases where an MHRA compliance check was completed before this guidance came into effect on 1 January 2025, the applicant should request written confirmation from the paediatric team that the agreed UK PIP and agreed EU PIP are equivalent and include this along with relevant PIP decision documents (as noted above) in the regulatory application.

Submission of the EU PIP decision documents is required when there is no separate UK PIP (that is, one with an MHRA number) as the EU PIP decision was adopted as the UK PIP on 1 January 2021 and has not undergone any further changes since the date of adoption.

Submission of the EU PIP decision documents is also required when there is divergence between the UK and EU decisions. Applicants can seek further advice on specific cases of divergence as described in section 10 below.

10. Contact

For general enquiries about paediatric submissions including PIP and waiver applications, modification procedures, and compliance checks, contact the MHRA Paediatric Unit at ukpip@mhra.gov.uk.

For further information, contactour Customer Services Centre at info@mhra.gov.uk or call 020 3080 6000.

Procedures for UK paediatric investigation plan (PIPs)