Paediatric medicines in the post-Brexit world

Paediatric Investigation Plans

The legal requirements for UK Paediatric Investigation Plans (PIPs) from 1 January 2021 are set out in the Human Medicines Regulations 2012, as amended by the Human Medicines Regulations (Amendment etc.) (EU Exit) Regulations 2019.

Under the Human Medicines Regulations, results from an agreed PIP must be included in an application for UK marketing authorisation (MA) for a UK application for a relevant medicinal product which is an initial marketing authorisation for the purposes of a global marketing authorisation, or an application for a new indication, new pharmaceutical form or new route of administration in relation to a product which is already subject to an existing UK MA. This requirement can be waived or deferred – if so, the MA application has to contain a decision granting the deferral or waiver (including a decision from the European Medicines Agency granting a class waiver and confirmatory letter that the medicinal product falls under the class waiver). The UK government guidance, Format and content of applications for agreement or modification of a Paediatric Investigation Plan and requests for waivers or deferrals and concerning the operation of the compliance check from 1 January 2021, provides detailed information on the format and content for submissions relating to PIPs, including information on what should be provided in an application for marketing authorisation.

The requirement to include results from an agreed PIP do not apply to certain applications, being applications for generic medicinal products, certain medicinal products that do not qualify as generic, similar biological medicinal products and products in well-established medicinal use.

The purpose of a PIP is to ensure that there is necessary data supporting that the medicine or proposed new indication, pharmaceutical form or route or administration will be safe for use in children. Accordingly, regulation 50B of the Human Medicines Regulations 2012 (as amended) states that a PIP must:

1. specify the timing and measures proposed to assess the safety, quality and efficacy of a medicinal product in the paediatric population; and
2. describe any measures to adapt the formulation of the medicinal product so as to make its use more acceptable, easier, safer or more effective for different subsets of the paediatric population.

After 1 January 2021, UK PIPs will be submitted to the MHRA. The requirements for scientific content and assessment will be kept in line with the EMA guidance documents, as confirmed in the UK government guidance, Procedures for UK Paediatric Investigation Plan (PIPs) from 1 January 2021 (1 September 2020). It is also confirmed that the UK will follow the principles as published in the European Commission’s Guideline on the format and content of applications for agreement or modification of a paediatric investigation plan and requests for waivers or deferrals and concerning the operation of the compliance check and on criteria for assessing significant studies.

If a UK PIP is required, it needs to be submitted to the MHRA no later than upon the completion of the human pharmacokinetic studies in adults, according to regulation 50B of the Human Medicines Regulations 2012 (as amended).

EU-PIPs or modifications to PIPs that were submitted and agreed by the EMA before 1 January 2021 will be adopted as UK-PIPs on or after that date and resubmission to the MHRA will not be required. Where a valid request for an EU-PIP or modification or waiver has been made to the EMA, but no decision has been given before 1 January 2021 and the EMA Paediatric Committee has given a positive opinion with which the UK has concurred, the EU-PIP will be adopted as a UK-PIP and resubmission to the MHRA will not be required. If the EMA Paediatric Committee has given a negative opinion, the MHRA will treat this application as refused, though applicants can submit an updated PIP to the MHRA to address the reasons for refusal. Where a valid request for an EU-PIP or modification or waiver has been made, and the EMA Paediatric Committee has not yet given an opinion or where the UK disagreed with the opinion, the PIP should be resubmitted to the MHRA.

The government has prepared flowcharts showing the assessment pathways for UK-PIP submissions from 1 January 2021. The MHRA will aim to accept a positive EMA Paediatric Committee opinion for EU-PIPs and modifications. A focused assessment may be required which considers a number of factors including, in a non-exhaustive list, unmet UK paediatric needs, the incidence of the disease in the UK population, additional safety or efficacy concerns for the UK population, and the feasibility of performing the proposed paediatric studies in the UK only. The applicant can also request a full assessment by the MHRA. For an application for a UK-PIP from 1 January 2021 where there is no EU-PIP, a full assessment will be required.

The unmet UK paediatric needs 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 for rare diseases identified by the Department of Health and Social Care policy paper, UK strategy for rare diseases;
• product development in conditions identified as critically important in the Paediatric Regulation 10 year report;
• products which are intended to be authorised as orphan medicines.

The current EMA class waivers list will be adopted by the UK from 1 January 2021. Again, the MHRA will aim to accept a positive EMA opinion on a class waiver request. Where there is no EMA opinion or a negative EMA opinion, the applicant should request an assessment from the MHRA.

A positive EMA Paediatric Committee compliance check or interim compliance check will be adopted as the UK compliance check outcome unless subsequent modifications have led to divergence between the UK- and EU- PIPs. The timing of submission of compliance check outcomes should be noted. They should be submitted ahead of time or at the time of the UK MA application. The UK government has published guidance, referred to above, on the procedure and outcome of compliance checks. If there is scientific divergence between the agreed UK-PIP and the EU-PIP, or if there is no compliance check from the EMA Paediatric Committee, then a UK assessment is required.

The applicant’s paediatric study plan (PSP) agreed by the US FDA should be provided as part of the UK-PIP submission.

Paediatric studies

The amendments to the Human Medicines Regulations 2012 will require UK MA holders who sponsor a study involving the use in a paediatric population to submit the results of the study to the MHRA within six months of the trial ending. This requirement remains regardless of whether the study is part of a PIP, or whether an application for a paediatric indication will be made. To find out more about clinical trials in the UK post-Brexit, see our post here.

The procedural requirements, including the timelines and workflow steps, for the submission of paediatric studies results are detailed in the UK government guidance, Completed paediatric studies – submission, processing and assessment from 1 January 2021 (1 September 2020).

If prior to 1 January 2021 and pursuant to the European regulations, the results have been submitted to the EMA or the Coordination Group for Mutual Recognition and Decentralised Procedures – Human , then the process will continue to be assessed within the EU assessment framework. After such assessment,  the final assessment report issued under the EU framework should be submitted to the MHRA. The UK equivalent procedure will not be initiated unless the MA holder indicates that an urgent safety update of the product information is required.

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