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 from 1 January 2021

This guidance provides information on the format and content of paediatric applications in the United Kingdom (UK) from 1 January 2021. The legal requirements for UK-PIPs are set out in the Human Medicines Regulations 2012, as amended by the Human Medicines (Amendment etc.) (EU Exit) Regulations 2019 (HMRs).

UK aims to maintain alignment with the EMA definitions unless otherwise specified. In the UK, the following definitions apply to PIP and waiver applications. Aims to ensure that the necessary data are generated to demonstrate the quality, safety and efficacy of the medicinal product in the paediatric population.

Please note that, unless indicated in future, the MHRA will be following the principles from the EMA Policy on the determination of the condition(s) for a Paediatric Investigation Plan/Waiver.

2.1.2 MHRA Submissions and templates submissions to the MHRA should be made via the PIP section of MHRA Submissions homepage. If the MHRA Submissions homepage is unavailable for PIP submission, the applicant should use the PIP templates available and send the completed forms to: ukpip@mHRA.gov.uk.

The paediatric population is defined in the HMRs as "that part of the population consisting of persons under the age of 18 years". A single application should cover the proposed research and development programme for a future single marketing authorisation application. Where the product is developed in stages and for different conditions, the applicant may apply for separate PIPs.

You should ideally notify the MHRA as early as possible before the planned submission. The MHRA will aim to accommodate submissions with a short notification period.

You may also request a pre-submission teleconference prior to responding to a request for modification. This is not intended to be a review of all your scientific documents, but an opportunity to clarify the Regulatory and scientific requirements.

If you need to confirm whether an indication is part of a condition for an agreed PIP or waiver decision, please submit an electronic request. Please use the email subject heading 'confirmation of inclusion of an indication within an agreed condition'.

2.2.3 Type of product The type of product, for which the application is made (such as a chemical entity, a biological product, a vaccine, a gene therapy product, a somatic cell therapy medicinal product), should be specified. 

2.2.4 Details of the medicinal product Information on all different pharmaceutical forms, formulations, strengths and routes of administration under development, irrespective of future use in the paediatric population, should be provided.

For the paediatric product development, information on the proposed strength, pharmaceutical form, route of administration and formulation (including details on the proposed excipients) should be provided.

2.2.7 Orphan medicine status please indicate whether you intend to seek an orphan marketing authorisation for the medicinal product in the UK.

2.2.6 Advice from a regulatory authority relevant to development in the paediatric population Please provide the MHRA with any decisions, opinions or advice.

The UK aims to simplify the PIP application process for applicants by mirroring the submission format and terminology of the EU-PIP system. Applicants are encouraged to include any information relevant specifically to the UK. The scientific document (parts B to F) should be as concise and as short as possible, but still explicit and readable as a self-standing document.

Part B should set out, for each existing indication and proposed condition/indication, how the HMRs PIP requirements will be met. For products being developed for PUMAs, only the concerned paediatric subsets need to be addressed.

Different degrees of severity or stages of a disease would not be considered as distinct conditions. The need for a particular treatment modality can be considered a valid criterion to define a distinct condition.

Application should briefly discuss any potential differences or similarities between the adult and paediatric populations. Applicants should provide a sufficiently detailed description of the pharmacological properties and of the known or suspected mechanism of action.

Describe the similarities and differences regarding seriousness of the disease, aetiology, clinical manifestations and prognosis. The list of available treatments should be inserted into the two tables based on authorisation. The MHRA will assess whether the specific medicinal product is expected to be of significant therapeutic benefit to children and/or to fulfil a therapeutic need in children.

The application should include a comparison of the medicinal product in question with the current methods of diagnosis, prevention or treatment of the conditions that are the subject of the PIP indication. When assessing significant therapeutic benefit, the MHRA will take into account the nature and seriousness of the paediatric condition to be treated (or diagnosed or prevented) and available data on the medicinal product concerned.

UK PIPs may be limited to certain paediatric subsets based on therapeutic needs without a requirement to cover all subsets. A product-specific waiver will not be required if the product and the proposed indication are already covered by a class waiver.

This section should be an overall summary of the UK-waiver request, and a summary of your position. In accordance with the HMRs Regulation 50D(2)(a), a waiver may be granted if 'the medicinal product or class of medicinal products is likely to be ineffective or unsafe in all or part of the paediatric population'

The absence of available data on the safety or efficacy in the paediatric population will not be accepted as the sole justification for a waiver. Please include a summary of your position in this section.

Waiver may be granted if the medicinal product does not represent a significant therapeutic benefit over existing treatments for patients in the paediatric population. Justification for such a waiver should be based on a detailed discussion of the existing treatment methods particularly in the UK clinical setting.

UK-Paediatric Investigation Plan indication should be described for the paediatric subsets included in the Paediatric Investigation Plan. Please include a summary of your position defining the proposed indication in the paediatric population for the purpose of a UK-PIP.

All subsets of the paediatric population should be covered either by a UK-waiver (Section C) or a UK-PIP (section D) In this case, the application may be limited to certain paediatric subsets without a requirement to cover all subsets.

The application should take into account any existing scientific guidance/advice and standard PIP published by the MHRA and EMA. The application should include a review of any information on the product in the paediatric population.

This section should address selected aspects related to the administration of the product to the relevant paediatric subsets. The addition of a paediatric indication may result in the need for an age-appropriate pharmaceutical form.

This section should contain your position regarding the plans for quality-related studies for paediatric development. If the strategy is to create age-appropriate pharmaceutical form, formulation, strength or new route of administration, the necessary pharmaceutical development studies may need to be more extensive.

The standard non-clinical development should not be submitted or discussed unless it adds relevant information to the paediatric development. Please include a summary of your overall non-clinical strategy for supporting paediatric development.

Explain whether animal models exist, and if so whether they are appropriate to study the effect of the product. Justify whether there is a need for mechanistic studies, for example if a particular safety issue identified from non-clinical development or adult experience. Describe whether there are any safety signals, which would have an impact on the development in children.

This section should discuss and justify the strategy for the clinical paediatric development. The inclusion of paediatric patients (for example adolescents) in adult trials should be considered.

Describe if scientific advice was given (UK, EU, international) and if so, if it was followed. Discuss the use of sparse sampling, PK modelling and population PK if relevant. Consider the following aspects where relevant for pharmaco-dynamic studies.

Consider the following aspects where relevant for pharmaco-dynamic studies. Discuss the use of sparse sampling, PK modelling and population PK. Consider the following aspects where relevant for clinical efficacy and safety studies.

Describe the proposed safety studies in the appropriate subsets of the paediatric population. Discuss the follow-up studies, time periods and whether patients are treated or not during the follow-up.

You should propose timelines for the initiation and completion of each study, including either specific dates (month and year) or ranges of up to six (6) months. Further information, if available and appropriate to the stage of product development, should be provided on the following, justification of type of study, study design and methodology.

2.6 Part E - Request for UK-deferrals. This section is only required for a new PIP application. A deferral may be granted when it is appropriate to conduct studies in adults prior to initiating studies in the paediatric population.

Any request for deferral of the start or completion of studies or other measures should make clear to which study/measure the deferred timeline relates. Please note that a clinical study report is required for the MHRA to perform the compliance check.

Supporting documentation should be uploaded with the new PIP or full product-specific waiver. The annexes to an application should include where relevant. The Key Elements Form should be completed on the MHRA Submissions homepage for a new PIP application, or a request to modify an agreed PIP.

The scientific document (Parts B-F) should be used to provide the background information, justification, explanations, legal and technical requirements. The Key Element studies comprise Paediatric formulation development studies.

When the procedure for a new PIP, full product specific waiver, or modification of an agreed PIP is concluded, you will receive a licensing authority proposed decision. You will be given the opportunity to comment on the proposed decision and to make representation if you disagree with this proposed decision. The licensing authority will issue a final decision letter as the legally binding outcome document. Where the licensing authority adopts a favourable final decision on the modification of the agreed PIP as set in the Agency's latest decision, the new decision on the modified agreed PIP will supersede the previous decision.

When you are ready to submit your reply, email the MHRA with your re-submission. The re-submission documents should include the PIP number in the subject line're-start MHRA-XXXXXX-PIPXX-XX'.

If changes are required to the "Application for UK-Paediatric Investigation Plan" (form A) or the "Key Elements Form – applicant's proposal for UK-PIP decision", these changes cannot be made by the applicant. The templates are available to download from the PIP templates section of the PIP tile on the MHRA Submissions homepage. The Paediatric Co-ordinator will inform you of the new timelines after you have submitted the resubmission documents.

You will not be allowed to add a new active substance in a PIP modification. A request for a full product specific waiver is allowed as a request modification of an agreed PIP.

All proposed amendments to the PIP should be reflected in the modification template (see guidance below) The template is available to download from the PIP templates section of the PIP tile homepage.

Applicants should download the template 'request for modification to an agreed PIP' from the PIP templates section of the PIP tile homepage. Applicants should explain the lack of appropriateness or the feasibility issue underlying each key element for which modification is being requested. An assessment of the effect of both making and failing to make the proposed change should be provided.

Only changes requested in this document will be considered by the MHRA. For each study in the agreed PIP, or for a new proposed study: insert the study number and/or study identifier. For each current key binding element, you request to change, copy the exact wording of the key binding element from the Annex I of the preceding decision. For each key binding element in the request for modification, include justification for change(s).

If there are validation issues, for example missing/incorrectly filled in information or missing/incorrect documents we will contact you. If the modification request is adopted as a positive proposed decision this will go on to replace the existing agreed PIP. If the licensing authority issues a negative final decision on the modification request, the agreed PIP decision which is already in place will remain as the legally binding document.

If you accept the proposed decision, or do not reply within 28 days of date the proposed decision is sent to you, this decision will become definitive. If you do not wish to accept the proposed decision you have the right to make representations as outlined in the relevant section of this guidance.

You are allowed to submit a new application for the same medicinal product and same condition via with a new PIP, waiver, or modification submission if you wish. For certain medicines a PIP submission is not required as part of the marketing authorisation application. The requirement to submit a PIP is waived for specific medicines or classes of medicines that are likely to be ineffective or unsafe in part or all of the paediatric population.

You will be required to submit a full product specific waiver application in the UK, or a UK-PIP. If you subsequently have received an EMA positive opinion on the product specific waiver request this may be taken into account in the UK's assessment.

The confirmation of applicability request considers whether there may paediatric unmet need for a product. If the class waiver is considered applicable to your product, the confirmation document should be included with any subsequent marketing authorisation application.

A partial compliance check will cover all those measures, within the condition(s) that cover the therapeutic indication(s) included in the regulatory application.  Validation of an application may not require a compliance check procedure if none of the studies or other measures in the agreed PIP have a timeline for completion that precedes the date of submission of the application.

The compliance check will determine whether the documents submitted cover all subsets of the paediatric population. The documents submitted cover the existing and the new indications, pharmaceutical forms and routes of administration.

Report should indicate in the form of a table how each subset of the paediatric population has been covered by the documents referred to in regulation 50A(3) or a waiver or deferral as described in regulation 50A(5). A separate table should be included covering the applicant's position on compliance with the key elements and, where submitted with the marketing authorisation application, providing a cross-reference for each key element of the PIP to the location in the relevant module in the marketing authorisation application.

You are allowed to request the opportunity to make written or oral representations to the UK-CHM. If no request to make representations is made, if a request is withdrawn, or if you make a request but fail to provide appropriate documentation, the proposed decision will become definitive via a final decision letter. Marketing authorisation holders with an agreed UK-PIP who have received a deferral must submit annual reports to the MHRA.

This information should be submitted via the MHRA Submissions homepage using the annual report page, navigating from the PIP homepage.

Submit electronically with the UK-PIP procedure number to ukpip@mhra.gov.uk. For all cases, completion of the date, current applicant's name, signature and printed name of the Authorised contact person are required.

For amendments required for a change of applicant due to a new legal entity the date, new applicant's name, and the signature of and printed name of the authorised contact person are required. In case of the change of 'applicant' due to takeover by different legal entity, it is to be issued by the new legal entity to authorise the contact person. The applicant's name on the MHRA website will remain as per the UK decision.

The notification does not exempt an applicant from the obligation to complete the agreed UK-PIP, if this exists. The notification does not exempt an applicant from the obligation to complete the agreed UK-PIP, if this exists.

Source: MHRA guideline on 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 from 1 January 2021

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