Guidance

Procedures for UK Paediatric Investigation Plan (PIPs)

The process for applicants applying for a Paediatric Investigation Plan (PIP) modification or waiver.

• From: Medicines and Healthcare products Regulatory Agency
• Published: 31 December 2020

The guidance also covers information for applicants or companies with an agreed EU-PIP opinion conferred prior to 1 January 2021.

General approach to UK Paediatric Investigation Plans

The PIP application process for applicants is simplified by offering an expedited assessment where possible, and by mirroring the submission format, content and terminology of the EU-PIP system..

The MHRA is taking decisions on PIP and waiver opinions, modifications and compliance statements to support paediatric market authorisation decisions, while acknowledging that Northern Ireland continues to be part of the EU’s system for paediatric medicines development including agreement of EU paediatric investigation plans (PIPs) or waivers.

The format and submission procedure for PIP applications to the MHRA is discussed in separate published guidance. Applicants should include information relevant specifically to the UK, particularly with respect to any areas of unmet therapeutic need that this product intends to cover [Section 6 of this document].

This guidance addresses the common scenarios that may occur when a UK paediatric procedure is submitted to the Medicines and Healthcare products Regulatory Agency (MHRA).

A case by case discussion should always be considered for any paediatric submissions to the MHRA that do not fall into any of the prespecified criteria listed below.

Parallel submission of PIPs to EMA and MHRA is strongly supported to allow robust parallel assessment and finally alignment of the agreed paediatric plans across jurisdictions.

Submission to MHRA is through a dedicated PIP portal in MHRA Submissions. Further step by step information on the process of submitting PIPs via the MHRA submissions portal is available in a separate, published user reference guide available via the PIP portal.

Section 1: PIP submissions

1.1. EU-PIPs, modifications to PIPs and full product specific waivers with completed EMA assessments before 1 January 2021

EU-PIPs, modifications and full product specific waivers with an EMA decision agreed before 1 January 2021, will be adopted as UK-PIPs on or after that date:

• These PIP applications will not require re-submission to the MHRA.

Where a valid request for an EU-PIP or modification or waiver has been made to the EMA, but no EMA decision has been given before 1 January 2021, the EU-PIP will be adopted as a UK-PIP if the EMA Paediatric Committee (PDCO) has given a positive opinion before 1 January 2021.

• These PIP applications will not require re-submission to the MHRA.

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

• In this case, the MHRA will treat the application as refused. However, applicants can submit an updated PIP to the MHRA which addresses the reasons for refusal.

• EU-PIPs which become UK-PIPs under these transitional provisions 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.

1.2. UK-PIP submissions after 1 January 2021

The MHRA is accepting PIP applications submitted via the MHRA Submissions portal.

According to Regulation 50B (3) of the Human Medicines Regulations 2012, as amended by the Human Medicines (Amendment etc.) (EU Exit) Regulations 2019 (HMRs), including transitional provisions, applications for the agreement of a paediatric investigation plan 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.

For details on the application please read published guidance on the required format and content.

When a PIP application is submitted to MHRA, information should be provided on whether there is:

• an agreed EU-PIP and the opinion and supporting documentation is included
• an ongoing EU-PIP assessment, its timeline in the PDCO assessment cycle (i.e. day 30, 60, clock stop, day 90 or 120)
• any current scientific divergence between the submitted PIP application and the EU-PIP

This information will be used to establish the MHRA assessment process as described in Sections 1.3 to 1.4.

The assessment pathways for UK-PIP submissions from are Annexes I and II (PDF, 90.9 KB, 2 pages).

1.3. PIP submission with agreed PDCO opinion from 1 January 2021 or ongoing assessment at EMA from 1 January 2021

In special circumstance when there is a delay in the PIP submission to the UK, in principle the MHRA will aim to maintain alignment with a positive PDCO opinion, if one is reached before the MHRA assessment is completed..

However, divergence could occur as we will take decisions for PIPs based on national and NHS paediatric public health needs.

• unmet UK paediatric needs [Section 6 of this guidance];
• paediatric only development particularly for an innovative product (such as a new drug class, mechanism of action)
• the incidence of the disease in the UK population
• the relevance of the scientific arguments by EMA / PDCO in the summary report (SR) to the UK paediatric 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)

A full assessment may be requested by the applicant.

1.4. UK-PIP with no EU-PIP from 1 January 2021

This section applies if there is no corresponding EU PIP submission or if the PDCO opinion is negative.

Full assessment of the UK-PIP is required.

The applicant should additionally clarify if:

• there has been a previous negative EMA / PDCO PIP opinion
• there was a withdrawn EU-PIP prior to the adoption of an EMA/PDCO opinion
• the current UK submission has been updated since the previous negative or withdrawn EU-PIP
• the applicant has included the previously withdrawn or negative EMA / PDCO PIP SR as part of the supporting documents in the MHRA submission
• during assessment, consideration will be given to the scientific discussions of the EMA / PDCO which led to the negative opinion or the withdrawal of the EU-PIP

If the applicant chooses to submit to the MHRA and has a negative PDCO opinion, the applicant should consider incorporating changes to the UK-PIP, for the elements that received a negative PDCO assessment.

Section 2: PIP Modifications

2.1. Modification of an adopted or agreed UK-PIP

According to Regulation 50B (6) of the UK’s Human Medicines Regulations 2012, as amended by the Human Medicines (Amendment etc.) (EU Exit) Regulations 2019 (HMRs), including transitional provisions, 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.

For both adopted and agreed UK-PIPs:

When a PIP modification is submitted, it should be confirmed if there is:

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

Modifications submitted for UK-PIPs where there is an EU-PIP should include the most recent PDCO opinion and PIP SR.

For Agreed UK-PIPs, there will be either a focused assessment in cases where the EU opinion for the initial UK-PIP was accepted by the MHRA or a full modification assessment in cases where the initial UK-PIP underwent full assessment.

The applicant may request a full assessment.

2.2. Requests for a PIP modification from 1 January 2021
In principle, the MHRA will aim to accept a positive PDCO opinion on modifications in cases where the initial UK-PIP was agreed on the basis of an agreed EU-PIP. A focused assessment may be needed if the criteria in Section 1.3 are met.

If the PDCO opinion is negative whilst the UK assessment is ongoing:

• The applicant has the option to withdraw the UK-PIP modification request or continue with the MHRA assessment
• Once a PIP has been withdrawn, a new UK-PIP modification can be submitted and will undergo review using the same assessment criteria discussed in Section 1.3 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

2.3. PIP modification with no agreed EU PIP modification

If there is no agreed EMA modification opinion a full assessment of modification will be required.

Section 3: Waivers

3.1. Submission of Paediatric Class Waiver

The current EMA class waivers list will be adopted by the UK from 1 January 2021.

In principle, the MHRA will aim to accept a positive EMA opinion on a class waiver request. Where there is no EMA opinion, a MHRA assessment will be undertaken.

For a negative EMA opinion on whether a Class Waiver applies:

• the applicant should submit a full product specific waiver request for MHRA assessment which should include 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 focused or full assessment is required

3.2. Submission of full product specific waiver

Sections 1.2 to 1.4 also apply to MHRA submissions for full product specific waivers.

For an EU full product specific waiver with a positive PDCO opinion or EMA decision before 1 January 2021.

• These will be adopted as a UK full wavier. No submission to the UK is required.

Section 4: Compliance Check

4.1. Adopted UK-PIP Compliance check (CC)

According to Regulation 50A (3) of the UK’s Human Medicines Regulations 2012, as amended by the Human Medicines (Amendment etc.) (EU Exit) Regulations 2019 (HMRs), including transitional provisions, applicants must submit a CC application to the MHRA where one is required for validation of the UK MA application.

A positive PDCO CC or interim CC will be adopted as the UK CC outcome unless subsequent modifications have led to divergence between the UK- and EU-PIPs.

However, the applicant must pay particular attention to the agreed timelines of those measures which would need to be completed after the PDCO CC to ensure compliance on the date of the UK Marketing Authorisation (MA) submission.

The PDCO compliance outcome documents should be submitted ahead of, or at the time of MA application via the PIP portal of MHRA Submissions (user guides available via the PIP tile). The format and submission procedure for PIP applications to the MHRA is published separately.

At the end of the CC procedure an MHRA compliance report will be issued to the applicant with either an outcome letter (for partial CC) or a decision (final or full CC).

4.2. Agreed UK-PIP CC

According to Regulation 50A (3) of the UK’s Human Medicines Regulations 2012, as amended by the Human Medicines (Amendment etc.) (EU Exit) Regulations 2019 (HMRs), including transitional provisions, applicants must submit a CC application to the MHRA where one is required for validation of the UK MA application.

A UK assessment is required for full or interim CC if:

• there is any scientific divergence between the agreed UK-PIP and the EU-PIP
• there is no PDCO CC
• in the case of an interim CC, there are additional key measures completed prior to UK MA submission.

The MHRA will adopt the PDCO CC outcome if:

• there is a positive PDCO CC
• the UK-PIP is equivalent to the EU-PIP
• for interim CC, there are no additional key measures completed prior to UK MA submission that requires further CC assessment.

Applicants are encouraged to request a CC ahead of submission of an MA application where one is required for validation. This should be submitted via the PIP portal of MHRA Submissions. At completion of the CC procedure, the MHRA will issue compliance outcome documents similar to those noted in Section 4.1 above.

4.3. Non-Compliance

• For non-compliance due to (minor) administrative issues, or discrepancies that do not affect the scientific conduct of the study, a streamlined assessment will be proposed at the time the applicant is informed of the noncompliance outcome
• This streamlined assessment will combine a shortened modification procedure with a rapid CC
• 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 opinion with those of the completed study report
• A rapid CC will be offered at the end of a positive modification agreement

4.4. Statements of compliance

An MHRA statement of compliance when all of the agreed PIP measures have been completed, will be issued, if appropriate, when an MA application (initial, extension or variation) is granted:

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 UK-PIP.

Section 5: Paediatric Study Plans (PSP)

5.1. Paediatric study plans (PSP)

Regarding the applicant’s paediatric study plans (PSP) agreed by the US Food and Drug Administration (FDA):

• Applicants should provide the agreed PSP as part of their UK-PIP submission

Section 6: 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, including those for rare diseases identified under the auspices of the Department of Health and Social Care (DHSC) policy paper - UK strategy for rare diseases
• product development in conditions (or paediatric groups) identified as critically important in the Paediatric Regulation 10 year report
• products which are intended to be authorised as orphan medicines
• products that fulfil the criteria of promising / innovative new products and are part of an accelerated MHRA submission or assessment pathway

The legal requirements for UK-PIPs are set out in the Human Medicines Regulations 2012, as amended by the Human Medicines Regulations (Amendment etc.) (EU Exit) Regulations 2019 (HMRs), including transitional provisions.

UK paediatric requirements webinar recording which took place on 29 October 2020:

UK paediatric requirements webinar recording which took place on 29 October 2020.

Contact

For general enquiries about paediatric submissions including PIP and waiver applications, modification procedures, and compliance checks, contact the MHRA Paediatric Unit at [email protected].

For further information, please email our Customer Services Centre at [email protected] or call 020 3080 6000. Alternatively, contact your Trade Association by emailing:

• Association of the British Pharmaceutical Industry (ABPI): [email protected]
• British Generic Manufacturers Association (BGMA): [email protected]
• BioIndustry Association (BIA): [email protected]
• Clinical & Contract Research Association (CCRA): [email protected]
• Ethical Medicines Industry Group (EMIG): [email protected]
• Health Food Manufacturers’ Association (HFMA): [email protected]
• The National Pharmacy Association (NPA): [email protected]
• Proprietary Association of Great Britain (PAGB): [email protected]

Published 31 December 2020