Format and content of paediatric investigation plans and related applications in the United Kingdom (UK)

Question 1

1.  Definitions

Accepted Answer

In the UK, the following definitions apply to PIP and waiver applications:

Paediatric investigation plan (PIP)

This is a development plan which consists of timing and measures proposed to assess the quality, safety and efficacy of a product in all, or some subsets of the paediatric population. It aims to cover a paediatric therapeutic need, and to ensure necessary data are obtained through paediatric studies to support the authorisation of a medicine for children.

Adopted PIP

EU PIPs which were agreed by the European Medicines Agency (EMA) prior to exit day, were adopted as UK-PIPs on 1 January 2021. These are referred to as adopted UK-PIPs.

Agreed PIP

New PIP submissions after 1 January 2021 that have been assessed and agreed by the MHRA, are referred to as agreed UK-PIPs.

Compliance check

It is a check that is required once the paediatric plan or study is complete, to confirm that companies comply with the agreed measures listed in each PIP. These checks are necessary and must be completed before the applicant can apply for a marketing authorisation (MA) or certain line extensions, or variations to an existing marketing authorisation.

Class Waiver

Class waivers are an exemption from the obligation to submit a PIP request, for classes of medicines intended for specific conditions. When the intended use is covered by a class waiver, applicants are not required to submit an application for a PIP to the MHRA for the condition covered by the class waiver. The current EMA Class waiver list has been adopted by the MHRA.

Waiver (Product specific)

A waiver allows an exemption for development of a medicine in children, when it is not needed or is not appropriate. For example in diseases or conditions that only affect the adult population. They can be requested for a subset of the paediatric population (a partial waiver) or all subsets (a full waiver).

Deferral

A deferral allows an applicant to delay development of the medicine in children until, for instance, there is enough information to demonstrate its effectiveness and safety in adults. However, even when studies are deferred, the PIP will include details of the paediatric studies and their timelines. Completion of the measures will trigger the operation of the compliance check.

Condition

Any deviation from the normal structure or function of the body, as manifested by a characteristic set of signs and symptoms, typically a recognised distinct disease or a syndrome.

Paediatric Investigation Plan indication

The proposed indication in the paediatric population for the purpose of a PIP, and at the time of submission of the PIP, within a specific condition.

Proposed indication

The indication for use in adults, as proposed by an applicant at the time of submission of the PIP/waiver application. In cases of a completed or ongoing adult development, this is the starting point for identifying the condition for potential paediatric use.

Key elements

Each measure in a PIP may contain one or more specific key elements, which are binding in the Decision and provide the basis for the operation of the compliance check.

Measure

Any study or other obligation (for example, a requirement to set up a registry), which is included in the PIP, with a view to ensuring that the necessary data are generated to demonstrate the quality, safety and efficacy of the medicinal product in the paediatric population.

Study

Any measure that is designed to answer a specific scientific question and is performed in accordance with a predefined methodology. This includes, for example, interventional and non-interventional studies, non-clinical studies, extrapolation studies, modelling and simulation studies, development of specific paediatric pharmaceutical forms and formulations.

Extrapolation Plan or Study

A plan involving the use of extrapolation of data from source population (adults) to support the use of the medicinal product in a target population (children). An extrapolation study may be based on case series, meta-analyses, systematic reviews, and modelling and simulation studies.

Modelling and simulation study

A study with the objective of quantifying the medicine/system/experimental design, in order to:

understand and estimate its properties
optimise and predict future experimental outcomes, and
aid regulatory, medicinal product development and use decisions

MHRA Provisional Decision

Contains the initial decision of the MHRA on the PIP or relevant paediatric procedure. This is sent to the applicant for review, comments and amendments if required, before finalisation.

MHRA Final Decision

Includes the MHRA Provisional Decision, Final Decision Letter and Annexes. A public version of the Decision with the confidential information removed is available.

Assessment

Full assessment: All aspects of the PIP are assessed independently. This includes dossiers which are not considered to include the most up to date information available.

Targeted assessment: Selected areas of the PIP and scientific document are assessed depending on the clarity of the discussions (from the Applicant, EU assessors and non-EU assessors), or where the content reflects UK specific issues or regulatory requirements that need to be addressed.

Question 2

2.  Format and content of applications for agreement on or modification of a paediatric investigation plan and requests for waivers and deferrals

Accepted Answer

2.1 General principles and format

2.1.1 Structure of format

Applications for agreement on or modification of a PIP, or requests for waiver or deferral and combinations of these, should be accompanied by particulars and documents in accordance with this guideline. Depending on the type, applications should consist of some or all of the following sections:

Section 1: Administrative and product information (Section A of the online application)
Section 2: Overall development of the medicinal product
Section 3: Application for a product-specific waiver
Section 4: Proposed paediatric investigation plan.
Section 5: Request for deferral
Section 6: Annexes

Section 1 (Online Section A) should be filled in online using the PIP application/Waiver application/Modification application in the MHRA Submissions homepage. Depending on the type of application, the relevant sections of Section 2 to 6 should be completed by downloading and filling in the scientific document template described in the next section. It is not necessary to also complete the Word template version of this section.

Sections and/or subsections that are not relevant for the specific application can be left empty or stated as ‘Not Applicable’.

For a new PIP application, Sections 1 (Online Section A) to 6 must be completed.
For a full product-specific waiver request Sections 1, 2, 3 and 6 must be completed.
For a request for modification of an agreed PIP only section 1 is applicable; specific instructions on requirements for a modification are in section 2.12 of this guidance.
For a request for confirmation of a class waiver, only section 1 is applicable; specific instructions on requirements for a class waiver are in section 3 of this guidance.

2.1.2 MHRA Submissions and templates

Paediatric submissions to the MHRA must be made via the PIP section of MHRA Submissions homepage using the appropriate procedure type (PIPs, Waivers, Modifications, Compliance Checks, Annual Reports). For general help, support and technical issues relating to the MHRA Submissions homepage please use the relevant link on the 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.

PIP related templates are available to download from the PIP templates section of the PIP tile homepage. The Scientific Document is required for an initial PIP application or request for a product-specific waiver (where only Sections 2, 3, and 6 required). For a request to modify an agreed PIP, the Request for modification of an agreed PIP template must be used. For confirmation of a class waiver, the request for confirmation of a class waiver template must be used.

Where a template is required, Word and PDF versions of the completed form must be uploaded to the relevant application in the MHRA Submissions portal.

2.1.3 Supporting information

The application should be based on all available information relevant to the evaluation, whether favourable or unfavourable to the product and its development. This includes details of any incomplete or discontinued pharmaco-toxicological tests, or clinical trials or other studies relating to the medicinal product, and/or completed trials concerning indications not covered by the application.

The amount of available information relevant to applications will differ substantially, depending on whether a medicinal product is in early clinical development or already authorised, and is being investigated for new, or extended uses. Therefore, the level of detail expected in the application may differ significantly in line with the specific development stage of the product when the application is submitted.

The application should

provide all annexed documents in electronic format - text, pdf or zip files may be uploaded.
provide individual files rather than merging into one document.
avoid scanned physical documents– the MHRA recommends 300 dots per inch, black and white where this is unavoidable (such as in copies of signed documents).
avoid using password protected files – where this cannot be avoided, please send the password to ukpip@mhra.gov.uk.
where applicable, include a reference list in alphabetical order based on the first author’s surname and year – references should be saved individually with first author’s surname first as the file name with year.

There is a maximum character limit of 215 characters for filenames of uploaded documents. Filenames must only contain the following characters: a-z, A-Z, 0-9, _, ., -.

2.1.4 Paediatric population

The paediatric population is defined in the HMRs as “that part of the population consisting of persons under the age of 18 years”. Applications subject to the requirements of

Regulation 50A(3), read with regulation 50A (1)(a) (initial marketing authorisation for the purposes of a global marketing authorisation)
Regulation 50A(3), read with regulation 50A (1)(b) (applications for a new indication (including a paediatric indication), a new pharmaceutical form or a new route of administration)

should cover all subsets of the paediatric population unless there are grounds for a waiver.

A single PIP 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. PIP applications for authorised products which will fall within the scope of Regulation 50A(3), read with regulation 50A (1)(b) (applications for new indications, pharmaceutical forms and routes of administration) should cover all existing and new indications, pharmaceutical forms and routes of administration, with a view to agreement on a single comprehensive PIP.

The paediatric population encompasses several subsets, as defined e.g. in international guidelines, for example ICH Guideline E11, (available at www.ich.org):

pre-term and term neonates from 0 to 27 days
infants (or toddlers) from 1 month to 23 months
children from 2 years to 11 years
adolescents from 12 up to 18 years

However, when it is considered more appropriate to use different subsets (for example, based on gender or stage of pubertal development), this may be acceptable, but the choice of subsets should be explained and justified.

A PIP application intended to support a future paediatric use marketing authorisation (PUMA) (Regulation 50E) may be limited to certain paediatric subsets; it is not required to address all subsets.

2.1.5 Coverage of application

The PIP application may include a request for a partial product-specific waiver for one or more paediatric subsets and/or indication(s). For a full product specific waiver (i.e., in all paediatric subsets) or class waiver application please select and complete the relevant Waiver Application from the MHRA Submissions homepage. Additionally, a PIP may include a request for deferring some or all of the measures.

2.1.6 Preparing the application

Although applicants must complete the online Letter of Intent as part of the application to generate the MHRA procedure number, a 2 month pre-submission notification period is no longer required for UK PIP submissions. However, it is advised that applicants notify the MHRA as early as possible before a planned Regulatory Application so that the intended UK-PIP submission is expected by the MHRA, and can be accommodated into specific procedural timelines. Submission dates and assessment timelines are published under the PIP Submission Guidance section of the MHRA Submissions homepage, and are no longer fully aligned with the EMA submission dates.

At the time of application to the MHRA, applicants should inform the MHRA if there is an ongoing paediatric study plan with another regulator such as an EU-PIP, waiver, or request for modification to an agreed PIP procedure.

Pre-submission advice can be obtained when a PIP/modification application is almost ready for submission, and there is a need to discuss regulatory or administrative issues not answered by MHRA guidance, in order to smooth the validation process. However, in the first instance, written advice would be provided by the Paediatric Team for such requests. This advice is not intended to be a review of all applicant scientific documents, but an opportunity to clarify the regulatory and scientific requirements, and ensure applicants are able to answer all the points in the Request for Modification (RfM).

Pre-submission teleconferences may be requested by applicants under certain circumstances. To request a pre-submission meeting before submitting a new PIP or waiver, or a modification of an agreed UK-PIP please contact the MHRA Paediatric Unit at ukpip@mhra.gov.uk.

Applicants may also request a pre-submission teleconference prior to responding to a request for modification if there are points of clarification regarding the request.

Applicants may suggest tentative dates, but the MHRA may not always be able to accommodate these.

If the request is granted, the MHRA will contact the applicant with a timeslot. Once confirmed, applicants will need to provide at least 14 days before the meeting:

a list of questions for the MHRA
a list of participants
if applicable, a draft application (Section 1, Sections 2-6 , and Key elements form)

Please note that the MHRA will ask applicants to send a meeting summary within 15 working days after the teleconference.

The MHRA also offers scientific advice, including protocol review. The scientific advice page on the MHRA website includes information on how to apply for scientific advice. There is a fee for this service, however there is no fee for paediatric only advice.

Applicants are also encouraged to consult paediatric experts, and the research community as well as patients’ groups, as early involvement may facilitate the development of the PIP, and include this discussion in the Scientific Document.

2.2 Section 1 (Online Section A) - Administrative and product information

All sections of the online Section A should be completed using MHRA Submissions homepage; where information is not available, this should be stated. Please refer to user reference guide on the PIP Submission homepage, for new PIP or request for a product-specific waiver or submission of PIP modification for further details on completing the online section. If all the relevant data cannot be accommodated into the online form, it is advised that a supplemental Word document is included in the application.

2.2.1 Name or corporate name and address of the applicant and contact person

The name and address of the applicant should be provided, together with the contact details of a natural person authorised to communicate with the MHRA on behalf of the applicant.

Please note that communication from the MHRA about the procedure and decision will only go to the contact person(s) entered in online Section A1. It may be preferable to use a suitable generic professional e-mail address to ensure communication is received in a timely manner. Please inform the MHRA of any change in contact details (see Section 7 Notification of administrative changes).

The contact details for interested parties, will become publicly available on publication of the decision. Therefore, a generic or suitable e-mail address and telephone number may be preferable.

Only one named contact can have access to the submission. The MHRA Paediatric Team cannot reassign cases to other authorised persons/contact details within a company. This request must be directed to the company administrator who will have the ability to reassign cases to other contact persons within the organisation.

2.2.2 Name of the active substance

The active substance should be stated by its recommended international non-proprietary name (INN), accompanied by its salt or hydrate form if relevant. If no ‘recommended’ INN exists, the British or European Pharmacopoeia name should be provided or, if the substance is not in the British or European Pharmacopoeia, the usual common name should be used. In the absence of a common name, the exact scientific designation should be given. Substances without an exact scientific designation should be described by a statement of how and from what they were prepared, supplemented where appropriate by any relevant details.

In addition to the common name or scientific designation, the applicant may also submit the company or laboratory code. However, the company or laboratory code cannot be used as the sole identifier of the active substance.

Preliminary names only may be provided, if necessary, in view of the deadline for submission of the applications. All successive name changes must be provided in any future applications related to the initial UK PIP application.

For commercially sensitive reasons, if applicants do not wish to have the name of the substance published, please include this request in the cover letter along with the alternative name of the active substance to be used in the published Decision document.

2.2.3 Type of product

The type of product for which the application is made (e.g. a chemical entity, a biological product, a vaccine, a gene therapy product, a somatic cell therapy medicinal product) should be specified. In addition, the pharmacological target and mechanism of action should be specified where possible. Where a pharmaco-therapeutic group and anatomical therapeutic chemical (ATC) code have been assigned, these should be included.

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.

2.2.5 Marketing authorisation status of the medicinal product

Information on the MA status of the medicinal product should be provided. Details should be provided of any regulatory measures restricting for safety reasons the use of the medicinal product inside or outside the UK. This includes the suspension, revocation or non-renewal of the MA, prohibition on supply, withdrawal of the medicinal product, a new contra-indication, a reduction in the recommended dose or a restriction on the indications of the medicinal product.

If an application is being submitted for a medicinal product which the applicant does not hold an MA in the UK:

the marketing authorisation status outside the UK, including information on all authorised indications, strengths, pharmaceutical forms and routes of administration, should be provided.

If an application is being submitted for a medicinal product: 1) for which the applicant already holds a marketing authorisation in the UK; and 2) which is protected either by a supplementary protection certificate (SPC) or by a patent which qualifies for the granting of a SPC; and 3) for which a future Regulatory Application will include one or more of the following, new indication(s), new route(s) of administration, new pharmaceutical form(s) (intended for children or not):

the marketing authorisation status inside the UK, including information on all authorised indications, strengths, pharmaceutical forms and routes of administration, should be provided.

If application is being submitted for a medicinal product: 1) which is not covered by a supplementary protection certificate (SPC) or a patent which qualified for the granting of a SPC; and 2) for which a Paediatric Use Marketing Authorisation (PUMA) will be sought, when the applicant is the marketing authorisation holder:

information should be provided on medicinal products authorised in the UK that contain the same active substance.

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 (including scientific advice and details of planned or pending advice) given by competent authorities, including those in EU- or non-EU countries, on the paediatric development of the medicinal product. This should include any written request for paediatric information issued by a regulatory body. It should also include any advice received for the adult population which may be of relevance for children, even if specific questions on paediatric development were not asked. Copies of any relevant documents should be annexed to the application.

2.2.7 Orphan medicine status

Applicants should indicate whether they intend to seek an orphan marketing authorisation for the medicinal product in the UK. In addition, indicate whether the medicinal product has been designated as an orphan drug by the European Commission. If so, the European Union Register of Orphan Medicinal Products number should be provided, and a copy of the decision should be included in the submission package. If orphan designation is being sought, this should be indicated. For pending applications the EMA’s Orphan Designation Procedure number should be provided. If there is another regulator’s Orphan designation, this should also be provided.

2.2.8 Planned application for marketing authorisation/extension of marketing authorisation/variation

For applications submitted for a medicinal product for which the applicant does not hold a marketing authorisation in the UK:

the planned or confirmed date of completion of the adult pharmaco-kinetic (PK) studies should be provided.
if PK studies are not relevant to the product, the date of completion of the Phase 1 programme in adults should be provided.
where no date can be provided or the PIP submission is late, a justification should be provided in the application form Section 1 (online Section A)– full justification should be included in the MHRA Scientific Document
enter the planned submission date of UK marketing authorisation application.
enter the planned submission dates of future UK regulatory procedures (if any) – include the date, the intended type of submission, and the planned indication.

For other application types:

only the planned submission date, type of submission and indication for UK marketing authorisation (or the next variation or extension) should be provided.

2.3 Section 2 (Scientific Document) – Overall development of the medicinal product

Unless otherwise notified, the scientific content required for MHRA Scientific Document is similar to that required by the EMA. However, applicants should include any information relevant specifically to the UK, particularly the areas of unmet therapeutic need that this drug intends to cover in the UK.

The scientific document should be as concise and as short as possible, but still explicit and readable as a self-standing document. The application should be particularly specific in Section 4 of the scientific document. The template for this document should be downloaded from the PIP templates section of the PIP tile on the MHRA Submissions homepage and uploaded with the application in both Word and pdf format. This document is to be used for the submission of an initial PIP or full product specific waiver application. Class waiver and Modifications of an agreed PIP require different templates.

For Sections 2, 3, 4 and 5 of the scientific document, if there is more than one condition, applicants should fill in these Sections for one condition then repeat sections (2-5) with the subsequent condition(s). Any request for a deferral should include the proposal of the studies, and timelines to be deferred.

Section 2 should set out, for each existing indication and proposed condition/indication, and each subset of the paediatric population, how the HMRs PIP requirements will be met. Section 2 must be completed for a new PIP application or a request for a full product-specific waiver.

Where the medicinal product is developed for use in children only, some of the information requested in Section 2 may not be available. For products being developed for PUMAs, only the concerned paediatric subsets need to be addressed.

Applicants should provide:

a discussion of the pharmacological rationale and mechanism of action as much as it known based on the current stage of development.
a general justification of the application submitted, including, where appropriate, the methodology chosen to identify potential conditions of paediatric need.
a description of the condition in the paediatric population, including similarities between adult and paediatric populations, and within the different paediatric subsets, prevalence, incidence including incidence in the UK if available, diagnosis and treatment methods across the world and UK specifically
details of the condition that the medicinal product is intended to diagnose, prevent or treat (diagnosis, prevention and treatment will generally be considered as separate conditions) including relevant information on the condition in adults.
where applicable, a reference to the condition according to an international disease classification system such as the WHO’s International Classification of Disease (ICD) or another well recognised system.

For common, well-described paediatric conditions, reference can be made to paediatrics textbooks without submitting detailed information.

The following points should be taken into account in the description of the condition. These points address, in particular, what constitutes a valid condition, as opposed to what would be considered as invalid subsets within a condition, and how these elements are linked to existing treatments and to the proposed indication:

the characteristics defining a condition should determine a group of patients in whom development of a medicinal product is plausible, based on the pathogenesis of the condition and pharmaco-dynamic evidence and assumptions.
recognised distinct medical entities would generally be considered as valid conditions. Such entities would generally be defined in terms of their specific characteristics, e.g. pathophysiological, histopathological, clinical characteristics.
different degrees of severity or stages of a disease would generally not be considered as distinct conditions.
the fact that a subset of patients exists in whom the medicinal product is expected to show a favourable benefit/risk would generally not be sufficient to define a distinct condition.
exceptionally, the need for a particular treatment modality (regardless of underlying diseases) can be considered a valid criterion to define a distinct condition, e.g. products to be used before or during bone marrow transplants, radiological or other diagnostic procedures.

2.3.1 Section 2.1. Discussion on pharmacological rationale and mechanism of action

Applicants should provide:

a sufficiently detailed description of the pharmacological properties, and of the known or suspected mechanism of action as far as known at this stage.
data/assumptions and a discussion of the impact of maturation aspects of pharmaco-kinetics and pharmaco-dynamics where applicable.
the main sites of action, potential expected side effects and pharmacodynamic drug interactions
information on whether the product is expected to act in the same or a different way in adults and children and in different subsets of the paediatric population
a discussion of the potential paediatric use of the product, based on its characteristics, in the relevant conditions

2.3.2 Section 2.2. Discussion on similarities and differences in the condition between populations

The application should briefly discuss any potential differences or similarities within the condition between the adult and the paediatric populations and/or between the different paediatric subsets.

These should be discussed with a view to extrapolating efficacy and/or pharmaco-kinetics, between adults and children, and the various paediatric subsets. Differences in aetiology, severity, symptoms, evolution, prognosis and response to therapy should be addressed where applicable.

Diagnosis, prevention and treatment of a disease will be considered as separate conditions. Please include a description of the aetiology of disease/condition, clinical manifestations, prognosis, epidemiology, and prevalence/incidence. Include information about the paediatric age range subset concerned by the disease / condition. If the disease does not occur in subsets of paediatric population, give the potential ground for waiver. Describe the similarities and differences regarding seriousness of the disease, aetiology, clinical manifestations and prognosis, variability in terms of genetic background. These should be discussed with a view to extrapolating efficacy and/or pharmacokinetics between adults and children, and the various paediatric subsets. Explain any differences based on e.g. disease pathophysiology on maturation (which organ, receptors).

2.3.3 Section 2.3. Current methods of diagnosis, prevention or treatment in paediatric populations

For each condition covered by the application, the diagnosis, prevention and treatment interventions that are available in the UK should be identified, making reference to scientific literature or other relevant information. This should include unauthorised treatment methods, whether pharmacological, surgical, dietary or otherwise, if they represent the standard of care (for example if mentioned in national or internationally recognised treatment guidelines).

The list of available treatments should be inserted into the two tables based on authorisation.

For not authorised or off label medicinal products please include:

active substance or INN
indication
source of recommendation (e.g. treatment guideline)

For authorised medicinal products please include:

invented name and active substance or INN
indication and age groups
type of authorisation (e.g. centralised, national, mutual recognition)

The invented name and the approved use of medical devices marketed in the UK should be provided if applicable.

2.3.4 Section 2.4. Significant therapeutic benefit and/or fulfilment of therapeutic needs

The applicant should discuss whether the specific medicinal product can 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.

Significant therapeutic benefit could be based on one or more of the following:

reasonable expectation for safety and efficacy to treat a paediatric condition where no authorised paediatric medicinal product is on the market
expected improved efficacy in a paediatric population compared to the current standard of care for the treatment, diagnosis or prevention of the concerned condition
expected improvement in safety in relation to either adverse events or potential medication errors
improved dosing scheme or method of administration leading to improved safety, efficacy or compliance
availability of a new clinically relevant age-appropriate formulation
availability of clinically relevant and new therapeutic knowledge for the use of the medicinal product in the paediatric population leading to improved efficacy or safety of the medicinal product in the paediatric population: needs, subsets
different mechanism of action with potential advantage for the paediatric population(s) in terms of improved efficacy or safety
existing treatments are not satisfactory and alternative methods with an improved expected benefit/risk balance are needed
expected improvement in the quality of life of the child

If unmet needs or the presence of significant therapeutic benefit are identified in some or all subsets, then please draw conclusions on the need to have a UK-PIP. Draw conclusions from Section 2 to identify unmet needs. Include a discussion of the feasibility of performing clinical trials in the condition, and whether the expected therapeutic benefit justifies paediatric trials in the condition. A discussion of whether new data need to be generated when there are existing data/indication (replicating data is of no benefit) should be included if relevant.

As experience with the use of the medicinal product in the paediatric population might be unavailable or very limited at the time of submission of the application, significant therapeutic benefit could also be based on well-justified assumptions. The application should explore these assumptions on the basis of reasoned arguments and relevant literature.

2.3.5 Section 2.5 UK-Paediatric investigation plan indication and selected paediatric subsets

The PIP indication should be described for the paediatric subsets included in the paediatric investigation plan. This Section should specify whether the medicinal product is intended for the diagnosis, prevention or treatment of the conditions in question.

The proposed condition(s) should be discussed in the context of current medical practice, paediatric needs and potential use, the mechanism of action of medicine, MedDRA classification system and relevant orphan medicine designation(s), starting from the indication(s) being developed and / or authorised for use in the adult population if applicable.

Applicants should include a summary of the position defining the proposed indication in the paediatric population for the purpose of a UK-PIP, and at the time of submission of the UK-PIP, within a specific condition. For example, “treatment of acute asthma episodes”, whereas the condition is simply “treatment of asthma”. Applicants should consider the need for data on the potential and correspondent paediatric use. This can be based on the mechanism of action of the drug, and should consider the potential for off-label use in children. It is not required that the UK-PIP is limited to the proposed wording of the adult indication, but it is assumed that there should be some relationship between development in adults and in the paediatric population.

Applicants should include a summary of the position regarding all paediatric subsets requiring a UK-PIP. All subsets of the paediatric population should be covered either by a UK-waiver (Form Section 3) or a UK-PIP (Form Section 4) unless the UK-PIP application intends to support a future UK-paediatric use marketing authorisation (UK-PUMA). In this case, the application may be limited to certain paediatric subsets without a requirement to cover all subsets. In addition to age, the selected paediatric subsets may be based on other variables, such as gestational age, pubertal stages, gender and renal function.

The age ranges to be studied should be justified and may vary depending on the pharmacology of the product, the manifestation of the condition in various age groups and other factors. In addition to age, the classification of the paediatric population may be based on other variables, such as gestational age, pubertal stages, gender and renal function, and this must be justified in the application.

2.3.6 Section 2.6 Summary of regulatory advice and/or network, expert, patient input

This should be aligned with the information provided in Section A (Section 1) of the online application.

Please include a very high-level summary of key outcomes described such as type of advice received (e.g. quality, non-clinical, clinical from MHRA, CHMP, SAWP, FDA, etc).

A summary of the main points of the advice should be provided with relevance to the proposed paediatric development, highlighting any divergence in points, if advice was not followed or it is superseded, and provide explanations why.

Any regulatory advice feedback documents received should be annexed to the submission.

Feedback from paediatric networks/experts, patients and their organisations, involvement of young people should be provided. Planned meetings with these groups should also be stated.

2.4 Section 3 (Scientific Document) - Applications for product-specific UK-waivers

This section should only be completed if applicable. However, please remember that all subsets of the paediatric population should be covered either by a waiver request or a UK-PIP proposal unless the UK-PIP application intends to support a future UK-paediatric use marketing authorisation (UK-PUMA). UK-PIPs intended to support applications for a UK-PUMA may be limited to certain paediatric subsets based on therapeutic needs without a requirement to cover all subsets.

2.4.1 Section 3.1. Overview of the UK-waiver request

A waiver may be issued with reference either to one or more specified subsets of the paediatric population, or to one or more specified indications/conditions, or to a combination of both. Requests for product-specific waivers should clearly define their scope in terms of paediatric subset and indication.

A product-specific waiver will not be required if the product and the proposed indication are already covered by a class waiver.

Applicants are advised to read the section on class waivers in this guidance and request from the MHRA confirmation of the applicability of a class waiver to a proposed development of a medicinal product in one or more adult conditions, where applicable.

If applicants intend to claim that measures in the paediatric population are not feasible, or appropriate, a detailed justification should be provided to support the claim.

This section should be an overall summary of the UK-waiver request, and a summary of the applicants position.

2.4.2 Justification for a product-specific UK-waiver

2.4.2.1 Section 3.2. Applications based on the disease or condition not occurring in the specified paediatric subset

In accordance with HMRs Regulation 50D(2)(b), a waiver may be granted if ‘the disease or condition for which the medicinal product or class of medicinal products is intended occurs only in adult populations’. On this basis, a justification for a waiver may be based on a detailed description of the incidence or prevalence of the condition in different populations. For waivers covering the totality of the paediatric population, the justification should focus particularly on the earliest age of onset of the condition. For waivers for specific subsets of the paediatric population, the justification should focus on the incidence or prevalence in the paediatric subsets identified in Section 2 of the scientific document.

2.4.2.2 Section 3.3. Applications based on lack of significant therapeutic benefit.

In accordance with HMRs Regulation 50D(2)(c), a waiver may be granted if ‘the medicinal product does not represent a significant therapeutic benefit over existing treatments for patients in the paediatric population’. On this basis, the justification for a waiver may be based on a lack of significant therapeutic benefit.

Justification for such a waiver should be based on a detailed discussion of the existing treatment methods particularly in the UK clinical setting. Reference can be made to the discussion in section 2: Significant therapeutic benefit and/or fulfilment of therapeutic need. Explain whether all paediatric needs in all subsets and conditions are met therefore implying there is no need for further development. If so, include an explanation based on the information from sections 2 and whether these match.

In particular, where existing medicinal products are authorised for use in children, applicants intending to request a waiver on this ground should justify in detail why the new product would lack significant benefit over the existing treatments.

2.4.2.3 Section 3.4 Applications based on a likely lack of safety or efficacy in part or all of the paediatric population

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’. On this basis, a request for a waiver may be based on a pharmaceutical rationale or (preliminary) data suggesting lack of efficacy or safety in the paediatric population.

The application should take account, for the different paediatric subsets, of the seriousness of the condition and the availability of other methods as stated in Section 2. All available evidence should be submitted to illustrate the likely lack of efficacy in the paediatric population as a whole or in subsets, as applicable. The justification should be based on effects observed in non-clinical models and studies, where available, or on a review of scientific literature including clinical studies.

The justification for a waiver based on the likelihood or evidence that the product is likely to cause harm may differ depending on experience with the product. Justification for a waiver on these grounds may include the pharmacological properties of the product or class of product, results of non-clinical studies, clinical trials or post-marketing data. The applicant should signal specific known or suspected safety issues.

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.

Applicants should include a summary of their position in this section. For efficacy justifications, include information on the likelihood of product to be ineffective based on Section 2 conclusions, and the rationale for lack of efficacy (for example pathophysiology, lack of receptors, etc.).

For justification based on safety, include information on the likelihood of the product to be unsafe, including any theoretical safety issues from a class effect. Also include any specific safety concerns from animal studies, or from adult population already identified.

2.4.2.4 Conclusion

After the discussion of the various potential grounds, provide a proposal for the most appropriate grounds for the waiver, respecting the hierarchy: first consider ground 1, then ground 2 and finally ground 3. Only one ground for each paediatric subgroup group should be proposed.

2.5 Section 4 (Scientific Document) - Proposed UK-paediatric investigation plan

This section is only required for a new PIP application. This Section should focus on the development of the medicinal product for the paediatric population. While applicants can discuss possible choices, there is no need to propose separate alternative developments in the application. Note that completion of this section is not required for a full product specific waiver application.

2.5.1 Section 4.1. Quality

2.5.1.1 Section 4.1.1. Existing pharmaceutical forms

This section should address selected aspects related to the administration of the product to the relevant paediatric subsets. Relevant guidelines on pharmaceutical development should be consulted to decide which measures could be relevant within the proposed strategy.

2.5.1.2 Section 4.1.2. Proposed pharmaceutical forms for paediatric use

The addition of a paediatric indication may result in the need for an age-appropriate pharmaceutical form, for example a dispersible form rather than a large tablet, or a mini-tablet of a new strength, because the existing pharmaceutical form, excipients or strength may be unsuitable for use in all or part of the relevant paediatric populations. This means that the suitability of the existing formulation, strength and pharmaceutical form should be discussed in the PIP. Consideration may be given to ethnic or cultural differences as regards acceptability, route of administration, acceptable dosage forms and excipients, in relation to the specific characteristics of the product.

Reference to relevant guidelines should be made as necessary when discussing paediatric pharmaceutical development.

The discussion should consider the existing or proposed pharmaceutical development of the product and address critical issues, such as:

the need for specific formulation, pharmaceutical form, strength or route of administration in relation to the chosen paediatric subsets/age groups and the benefit of the chosen formulation, pharmaceutical form, strength or route of administration
administration of the medicine to paediatric subsets (for example use of specific administration devices, ability to mix with food)
precision of dose delivery and/or dose accuracy for any pharmaceutical form, with regard to the anticipated paediatric dose and indicated age range.
timeframe for the development of an age-appropriate formulation/pharmaceutical form, where required.
discuss (if applicable) medical devices in relation to dosage accuracy and precision.
taste-making and acceptability (including palatability).

If it is not possible, based on scientific justifications, to develop a formulation/pharmaceutical form which is relevant and acceptable for paediatric use on an industrial scale, the applicant should state how it intends to facilitate the industry-verified or extemporaneous preparation of an individual ready-for-use paediatric formulation.

You should include a discussion of the ease of administration by parents, carers, schools and older children themselves as appropriate.

2.5.1.3 Section 4.1.3. Justification of components

The application should include a discussion of potential issues in relation to excipients and their (anticipated) exposure levels to be used in the paediatric population:

The necessity of each critical excipient, the use, and the quantity of excipient included in the paediatric formulation(s) planned for the paediatric population should be provided. This is particularly important for a new excipient and preservative
For critical excipients, a justification should be provided for the safety of each excipient in relation to maximum daily exposure and target age group, route of administration and duration of treatment.

2.5.2 Section 4.2. Non-clinical aspects

2.5.2.1 Section 4.2.1. Existing non-clinical data

This section should discuss the strategy for the non-clinical development which is needed to support paediatric use in addition to classical non-clinical development or existing data. If human safety data and previous animal studies are considered insufficient for reassurance on the likely safety profile in the intended paediatric age group, juvenile animal studies should be considered on an individual basis.

Reference to relevant guidelines on non-clinical development should be made as necessary when discussing non-clinical studies.

The standard non-clinical development should not be submitted or discussed unless it adds relevant information to the paediatric development, and is not covered elsewhere (for example in the annexed investigator’s brochure).

There should be a discussion of the need of reproductive toxicity and juvenile animal studies, and a discussion of the prerequisites to human administration and in particular paediatric administration, including whether this product is considered ‘high-risk’.

There should be clarification whether there is a need to study local tolerance (for example trans-cutaneous route of administration) and if there a need to study immunogenicity.

Justification should be provided on 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.

The following aspects should be discussed in the scientific document taking into consideration existing guidance.

Safety Pharmacology
Pharmacokinetics (PK)
Repeat-dose toxicity studies
Reproduction
Genotoxicity
Carcinogenicity

In the discussion of these aspects the following should be considered where relevant.

the need for proof of concept for use in paediatric populations, e.g. using non-clinical in vitro and/or in vivo models
the need for pharmaco-dynamic studies (e.g. to establish a dose relationship for a pharmaco-dynamic endpoint, if there is a reliable animal model to justify the choice of the most relevant species for potential juvenile animal studies)
the need for any paediatric-relevant safety pharmacology data (studies using non-clinical in vitro and/or in vivo models to investigate specific functions of the physiological system)
the need for toxicity studies to address specific endpoints, e.g. neurotoxicity, immunotoxicity or nephrotoxicity at a particular developmental phase

2.5.2.2 Section 4.2.2. Proposed non-clinical development

Please include a summary of the overall non-clinical strategy for supporting paediatric development.

2.5.2.3 Section 4.2.3. Justification of overall strategy and juvenile safety studies

If studies in juvenile animals are proposed, justification of the selected species and age of animals should be made. Explain whether animal models exist, and if so whether they are appropriate to study the effect of the product and to extrapolate the results. A weight of evidence (WoE) discussion is advised.

2.5.3 Section 4.3. Clinical aspects

2.5.3.1 Section 4.3.1. Existing clinical data and planned studies in adults

The application should outline the development of the medicinal product, including the pharmaceutical development which is relevant for paediatric development, completed clinical studies in adults and the results where available. A brief outline of the planned studies in adults should also be provided. This information may be provided in tabular format. The full study reports of completed clinical studies do not need to be provided; a summary of the results and a discussion of the implications for paediatric development should be sufficient. Full reports should be made available upon request. The application should consider any existing scientific guidance/advice and justify any deviation for the paediatric development.

The following aspects should be discussed, taking into consideration existing scientific guidance.

pharmacokinetic properties
pharmacodynamic properties
interaction with other medicinal products
summary of efficacy data
exposure-response analysis
summary of safety data (including risk minimisation measures)

In addition, the application should include a review of any information on the product in the paediatric population, making reference to scientific and medical literature or other relevant information, such as reports on use outside the terms of a marketing authorisation, medication errors, accidental exposures or known class effects.

2.5.3.2 Section 4.3.2. Proposed clinical development

This section should discuss and justify the strategy for the clinical paediatric development, in relation to the development in adults where applicable, and in relation to existing data and the potential to extrapolate. This should include critical aspects of study design and should present the strengths, advantages and disadvantages of the proposed clinical development. Where appropriate, the inclusion of paediatric patients (for example adolescents) in adult trials should be discussed. Please do not discuss here the individual studies. This Section is about the approach to and rationale for development. Also include, where relevant, justification for whether there is a need for proof-of-concept in humans.

The discussion in this Section should focus on:

possible complete or partial extrapolation from adult data to paediatric patients and between paediatric subsets
the interrelation, in terms of common studies, data and timelines, between development in adults and paediatric populations
where necessary, a discussion on how dosing in very young, and young children is determined and verified.
what data have been demonstrated so far, and which confirmatory data are expected.

Trial design should consider the safety of vulnerable groups whenever possible. Extrapolation approaches may be proposed with appropriate justification.

2.5.3.3 Extrapolation

This should include a discussion on the possibility for extrapolation to support development which should be focused on limitations and uncertainties in any relevant target population, taking into consideration the ICH Harmonised Guideline E11A on paediatric extrapolation.

The following structure below should be used when providing the respective reflections and data.

Summary of existing evidence

Disease similarity
Drug Pharmacology
Response to treatment
Safety considerations
Sources and types of existing data

Gaps in knowledge

Relevant risks and remaining uncertainties

2.5.3.4 Graphic overview of milestones and timelines

A graphic or tabular representation of timelines, in relation to adult planned development, non-clinical data availability and pharmaceutical form development milestones, should be provided.

2.5.3.5 Strategy for paediatric dose selection and PK/PD evaluation

In this section, discuss the dose-finding strategy, and proposed dosing regimen (for example according to weight, body surface area). Explain whether there are there any expected differences in exposure response, and disease progression between the adult and paediatric population which might have an impact for the development in children considering pharmacology, real word data/evidence (RWD/E) and literature data. Refer to ICH Harmonised Guideline E11A on pediatric extrapolation.

Discuss if there is a need for PD modelling and clinical trial simulations, and discuss any biomarkers for PK / PD. PK studies should be adequately designed with optimised sample sizes and sampling schedules.

2.5.3.6 Modelling and simulation analyses supporting paediatric development

In this section, describe the modelling and simulation (M&S) analysis proposed and role in the development.

If modelling and simulation studies are planned as a substantial (or exclusive) part of the PIP, justification should be here for the proposed objective, data to be used and methodology.

If extrapolation of efficacy is pursued through M&S, the methodology and how the analysis will be performed should be discussed here.

Definition of the relevant subsets for PK studies and discussion on the need for PK data in different subsets. Discuss the use of sparse sampling.

Discuss how models will be updated, and how assumptions made in the models are confirmed. Where modelling is used to characterise dose-exposure-response relationships, developmental maturation and disease progression should also be considered.

2.5.3.7 Proposed clinical studies

Please include a summary of the position on clinical efficacy and safety studies. Consider the following aspects where relevant:

the need for specific dose-finding studies
the selected efficacy and/or safety endpoints (primary or secondary), in each of the relevant paediatric subsets
issues of relevance across the proposed studies, such as use of placebo or active control, age appropriateness of endpoints, use of surrogate markers, use of alternative study design and analysis, potential need for short-term and long-term safety studies and differential risks by age group
issues related to the feasibility of the proposed studies (for example recruitment capacity)
any potential concern as to long-term safety or efficacy in the paediatric population
specific measures proposed to protect the paediatric population involved in development, for example the use of less invasive methods.

Describe any feasibility issues at this level of the development programme. In the case of trials with a proposed small number of participants include information justifying the approach, including whether any adaptive design is proposed.

Describe the proposed safety studies in the appropriate subsets of the paediatric population. Explain whether there are any safety signals which would have an impact for the development in children.

Specify the follow-up studies, time periods and whether patients are treated or not during the follow-up.

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
justification for the study population, relevant age groups or subsets included in the study (and of staggered inclusion where applicable)
justification of the dose of the proposed product and its regimen, and of the type of control (e.g. placebo or active control, with dose to be used)
description of the sample size/power calculation (as appropriate; with expected effect size in children) used to determine the proposed number of subjects (male/female). This discussion should include, where possible, a sensitivity analysis (a tabulation with varying assumptions and statistical parameters, and the resulting sample sizes)
justification of the proposed duration of treatment (and duration of post-treatment observation if included in the study)
justification of main inclusion/exclusion criteria
justification of the choice of outcome parameters/endpoints (primary, secondary)
justification and, if needed, a more detailed description of statistical methods than that contained in the key elements
discussion of options in the event of recruitment issues.

If common issue to several studies:

discuss comparator: placebo as control, or active comparator (authorised, not authorised/standard of care) in phase 3 trials?
discuss endpoint(s) if common to several studies (validated scales, non-invasive measures)
discuss duration of active treatment
discuss duration of long-term follow-up

Consider the following aspects where relevant for pharmaco-dynamic studies:

pharmaco-dynamic differences between adult and paediatric populations (for example influence of maturation of receptors and/or systems)
use of pharmaco-dynamic modelling and clinical trial simulations
discussion of any biomarkers for pharmaco-kinetics/pharmaco-dynamics
use of the pharmaco-dynamic approach, particularly where pharmacokinetics cannot be measured; and

For pharmaco-kinetic studies:

possibility of using sparse pharmaco-kinetic sampling
use of pharmaco-kinetic modelling and clinical trial simulations
use of population pharmaco-kinetics
discussion of age groups where more extensive studies are needed, for example due to expected high kinetic variability
pharmacogenetics.

2.5.3.8 Section 4.3.4. Other studies proposed

In this section include other proposed studies such as retrospective studies, literature analysis, etc., that does not fall under the previous sections. Also include here any Real World Evidence (RWE) sources if these have to be used.

2.5.3.9 Considerations for planned long-term follow-up

Based on the proposed development and the known safety profile, discuss relevant risks that could be important for the paediatric population for which post-authorisation studies are expected.

Explain any if there are any proposed long-term measures for follow-up on safety and efficacy, and if so, whether they should be part of the PIP or post-authorisation measures.

This can be reflected in Section 5 of the MHRA Decision

2.6 Section 5 (Scientific Document) - Request for UK-deferrals

This section is only required for a new PIP application; it is not necessary for a full product specific waiver request.

The deferral discussion should be with regard to the date of the planned UK Regulatory (MA) application regardless of route and not based on the timing of applications in other regulatory jurisdictions.

Where it is not planned that a study or other measure in the PIP will be initiated or completed before the submission of the corresponding UK marketing authorisation application in adults, a deferral may be requested for either the initiation or completion of the study or both. Requests for deferral should be justified on scientific and technical grounds or on grounds related to public health.

In accordance with Regulation 50C of the HMRs, a deferral may be granted when it is appropriate to conduct studies in adults prior to initiating studies in the paediatric population; or studies in the paediatric population will take longer to conduct than studies in adults.

For timelines, either specific months and years should be given, or a range of up to six months; timelines for initiation may also be expressed in relation to the development in adults.

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. Particular emphasis should be placed on the timing of the measures as compared with the development for adults, as expressed in the ICH guideline E11.

Please note that a clinical study report is required for the MHRA to perform the compliance check. This should be taken into account in the final timelines of submission.

2.7 Section 6 (Scientific Document) - References and Annexes

Supporting documentation should be uploaded with the new PIP or full product-specific waiver in the MHRA Submissions homepage. Specific guidance is given on the supporting documents for a request to modify an agreed PIP or for a Class waiver application in Section 2.12 and Section 3 respectively. The annexes to an application should include where relevant:

completed template for UK Scientific Document (in Word and pdf versions) – only Sections 2, 3, and 6 are required for a full product-specific waiver.
Completed template for UK-PIP procedures cover letter - requesting new PIP, a product specific waiver– please include full UK PIP number
letter of authorisation for the person authorised to communicate on behalf of the Applicant - this should be printed, signed, scanned and saved as a pdf
a signed copy of Form A is required – please print, sign, and scan the signature pages to submit electronically- the form does not need to be completed.
copy of Scientific Advice given by MHRA – if relevant
copy of Scientific Advice given by EMA’s CHMP – if relevant
copy of Advice/Opinion/Decision given by competent authorities of other countries – if relevant
copy of FDA written request – if relevant
copy of Decision on Orphan Designation from regulatory bodies – if relevant
copy of previous MHRA decision on Paediatric Investigation Plan– if relevant
Any agreed paediatric plans from the EMA (PDCO opinion, EMA Decision with annexes) or other regulators.
Risk Management Plan
Investigator’s Brochure most up-to-date version.

Please prove a list and copies of all literature references, articles, bibliography, etc. related to the scientific discussion:

use alphabetical order based on the first author’s surname and year
references should be saved individually using the first author’s surname and year - may be uploaded as a zip file containing all the individual references

2.8 Key Elements Form

The Key Elements Form must be completed for all studies online via the MHRA PIP submissions portal. This applies to an initial PIP application and for subsequent modifications of an agreed PIP. Applicants should only provide PDF or Word versions in the submission if they are not able to submit the Key Elements Form online, or as part of the part of the responses the MHRA’s request for modification (See Section 2.9), or due to character limitations where they cannot enter the full description of the measures online. A word version of the form, The ‘Template for key elements form - applicant’s proposal for a UK-PIP decision_2024.’ can be downloaded form the PIP Templates Tile of the MHRA PIP Submission Homepage.

The key elements form is used as the basis of proposing and forming the PIP decision. Applicants should propose the main features of the completed, ongoing, and future measures, and studies for paediatric development proposed to be included in the PIP decision. This should include the pharmaceutical development (quality), non-clinical, and clinical studies for children. Applicants should include short statements and the salient points, rather than excessive description. The Key elements form should not contain unnecessary details.

Depending on the specificities of the application, not all key elements may need to be addressed in every measure/study. In duly justified cases, further key elements may be required. This may apply in particular to advanced therapy medicinal products, new class of products, immunological medicinal products, radiopharmaceuticals and medicinal products based on human blood or plasma. This should be discussed on a case by case basis with the MHRA.

The scientific document should be used to provide the background information, justification, explanations, legal and technical requirements. Section 4 of the scientific document should include the discussion of the critical aspects, as well as strengths and limitations of the proposed and alternative features of the proposed measures / studies.

The Key Element studies comprise:

Paediatric formulation development studies:

a. Pharmaceutical form, formulation, strength, route of administration for development for paediatric use

b. Timelines for completion

Non-clinical studies:

a. Type of study

b. Objective and outcome measure

c. Test system

d. Route of administration and doses

e. Duration of dosing

f. Timelines for completion

Paediatric clinical studies:

a. Type of study

b. Study design and control

c. Main objectives

d. Study population and paediatric subsets in which the study will be conducted (with key inclusion and exclusion criteria)

e. Minimum number of study participants

f. Paediatric formulation used in the study, dose ranges, treatment regimes, route of administration

g. Minimum study duration

h. Primary endpoint, main secondary endpoints and time of assessment

i. Statistical plan

j. Timelines for completion

Modelling and simulation studies:

a. Model objective and description

b. Data to be used to build model

c. Methodology and software

d. Co-variates

e. Model qualification

f. Timelines for completion

Extrapolation studies*:

a. Type of study and design

b. Objective

c. Methodology

d. Study population and subsets

e. Minimum number of study participants

f. Timelines for completion

(*An Extrapolation Plan, which is a high-level overview of the extrapolation concept, can be presented in lieu of the study)

2.9 Procedural guidance for PIPs

The submission deadlines and timelines for procedures are located in the PIP Submission guidance tile of the MHRA portal and will be automatically emailed to applicants on full submission, successful validation and re-submission (for initial PIPs) of the application.

After the application form has been submitted for a new PIP or product specific waiver, and after the submission deadline for the month has passed, the MHRA Paediatric Team will assign an assessor, who will review and confirm the validity of the documents. This will occur in the interval between the submission deadline and the start of procedure date.

If there are validation issues, for example missing/incorrect information or missing/incorrect documents, the MHRA will contact applicants via the MHRA PIP communications mailbox which is linked directly to the application.

The e-mail will explain the validation issues, the deadline for a response, and the next steps to take. Validation correction responses (if required) shall be submitted via the PIP application by the indicated deadline.

If the issues are not resolved, this will lead to an invalid application, and a new application will need to be submitted.

Once validated, the procedure assessment clock will start, and the relevant application in the MHRA Submissions homepage will be locked. Applicants cannot make any further changes to the webpage or the submitted documentation at this point. However, applicants will still be able to edit the Key Elements, access the Documents section for upload, and download the MHRA documents and Applicant responses.

The automated timelines for the procedure that applicants receive are the planned outcome dates, which cover the Start (or Restart) of Procedure and First (or Third) Discussion dates of the procedure. The expected outcome date (for a Provisional Decision or Request for Modification) is aligned with the Date of the Second (or Fourth) MHRA Discussion. Further details regarding the dates for these discussions are found in the PIP Submission Guidance section of the PIP homepage

For an initial PIP application, applicants may be issued with a Request for Modification (RfM) after the initial assessment. This is followed by a clock-stop period during which further justifications or modifications to your proposals are required (see Section 2.10 below).

When the procedure for an initial PIP, full product specific waiver, class waiver, or modification of an agreed PIP is concluded, applicants will receive the MHRA Provisional Decision along with a summary report. Applicants will be given the opportunity to comment on the proposed decision and report, and to make representation if they disagree with this proposed decision (see section 2.12 and section 5). The MHRA will issue Final Decision documents with the Final Decision with Annexes 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.

Requests for an expedited review must be submitted via ukpip@mhra.gov.uk. Details including the PIP procedure number and the reasons for the request must be provided. An expedited review is not guaranteed as it is dependent on the complexity of the assessment and assessor availability. If there is a delay to the assessment, the Assessor will provide an update on the application via the MHRA PIP communications mailbox.

2.10 Interim PIP

There may be instances where all measures cannot be agreed during the initial PIP application, due to very early stage in development, and the absence of key data which can help inform clinical development in the paediatric population. In these cases, measures which cannot be defined should be scientifically justified including a description of the requirements needed to define these in the PIP. If this is accepted, an interim PIP can be agreed, with a high-level overall plan including at a minimum, a condition, a preliminary outline of planned studies based on available evidence and a PIP completion date.

However, timelines and key milestones must be agreed with the MHRA for the subsequent PIP modifications to include new data to the PIP and to define modify high-level /preliminary measures.

Such PIPs should be submitted the same way as the initial PIP, noted in section 2 of the scientific document and cover letter, with the same supporting information and a robust scientific justification for those PIP measures that cannot be defined in the application at the time of submission. However, the agreed PIP must be updated in a timely manner, as this will have implications for the validation of any subsequent Regulatory Applications and the conduct of the compliance check.

2.11 Request for Modification (RfM) of an initial PIP

After the initial assessment of an initial PIP application, the MHRA may request that applicants consider modifications to the proposed PIP. A list of questions and points for consideration will be e-mailed, along with the summary report. The procedure will go into clock-stop while applicants formulate a response including relevant changes to the key element form.

Applicants may request a pre-submission teleconference prior to responding if there are points of clarification regarding the request. It is generally expected that a response to the request for modification should be received within three months, however this is flexible, and more time may be required for substantial amendments. However, please notify the MHRA of planned response dates for planning purposes.

When applicants are ready to submit replies, please upload your responses and all relevant documents via the Documents section of the online submission. Applicants should inform the MHRA via the response to MHRA PIP communications mailbox that responses have been submitted.

The response documents should include.

a cover letter indicating when applicants would like to re-start the procedure – please include full PIP number
a response document to request for modifications, including a list of new references, in Word
applicants do not need to provide an updated copy of the scientific document as the response document should contain only replies and information relevant to the specific questions and issues raised by the MHRA during the assessment.
a copy of additional references in a single zip file - please do not include previously sent references.
additional supporting documents to support the responses.
an electronic copy of the e-form (Section A) - if changes are required – a copy of the template should be downloaded from Appian and sent in electronic format to the MHRA – do not attempt to change the webform on the MHRA Submissions homepage
electronic key elements form – if changes are required
Document checklist

As part of the RfM responses, if changes are required to the Key Elements and Section A of the online application, these updates cannot be made online by the applicant. Please download the “Template for application for UK-paediatric investigation plan or UK-product specific waiver” (form A) and/or the “Template for key elements form - applicant’s proposal for a UK-PIP decision”, from the PIP templates section of the MHRA Submissions homepage, complete, and upload these via the documents section of the online application in both Word and pdf format. If changes online Section A of the MHRA submission records of the PIP are needed, these will be implemented internally by the Assessor following the applicant’s written confirmation. This is to allow the system to generate the proposed decision document containing the finally agreed measures.

The Assessor for the procedure will update the PIP submission, and provide new timelines via automated email on re-submission of the documents.

2.12 Modification on an agreed/ adopted PIP

2.12.1 Request to modify an agreed PIP guidance

Once a PIP is agreed, it can be modified by the applicant. Regulation 50B(6) of the HMRs provides for requests for an agreed PIP to be modified where necessary. Such modifications are required where key elements of the PIP are unworkable or no longer appropriate. A request for modification of an agreed PIP is not necessary if the modification affects only aspects of a study or a measure that are not reflected in the currently agreed decision.

Submission of an application to modify the PIP will be particularly important if new information may have an impact on the nature or timelines for completion of one of the key elements in the licensing authority PIP decision.

The product’s authorisation information must reflect the current status – particularly if it has obtained a UK marketing authorisation since the preceding procedure.

Note that applicants will not be allowed to add a new active substance in a PIP modification. This would require submission of a new PIP. However, this may not apply to inclusion of new variant strains for vaccines (such as for COVID-19 or Influenza) as addition of strain variants can be included within a modification procedure, following discussion and confirmation with the MHRA’s Paediatric Team prior to the submission.

Changes to the route of administration or pharmaceutical form are also acceptable requests in a modification procedure.

A request for a full product specific waiver is allowed as a request modification of an agreed PIP if applicable based on new available evidence.

For the first Modification of an adopted UK-PIP (one where there is no MHRA number but only an EMA number prior to 01 January 2021) please quote the EMA number of the PIP in the online application.

For all subsequent modifications, and for the first modification of the agreed UK-PIP (i.e., one with there is an existing MHRA number) please use the MHRA Number of the latest MHRA Decision in the application, omitting any references to the EMA number in the online application.

Note that any EU-PIPs with numbers generated after 31 December 2020 will not be recognised on the system. If applicants should wish to refer to these numbers, please only include them in the cover letter.

Addition of a new request for modification within an ongoing modification procedure (i.e. without UK decision) usually cannot be accommodated due to the limited timelines for the assessment. However, simultaneous modifications can be accepted once these are discussed and agreed by the MHRA Paediatric Team in advance of the submission.

Applicants who wish to align an adopted UK-PIP with a current EU-PIP (which has undergone several modifications since 2021) can submit a group of agreed EU modifications consolidated into a single UK Modification submission.

2.12.2 Documents for a request to modify an agreed PIP

Applications to request a modification to an agreed PIP should be made through the MHRA Submissions homepage, first completing the letter of intent Section, which generates the UK-PIP number for the application. See section 2.1.6 ‘Preparing the application’ for additional guidance. You will then need to submit the amendments you are requesting to the agreed PIP, and their justification.

Applicants must submit as part of the submission package for a request for modification:

a completed copy of the ‘Template for request to modification of an agreed paediatric investigation plan’ submitted as Word and PDF versions
cover letter requesting a request for modification to an agreed PIP - please include full MHRA PIP number (or EU-PIP number if applicable)
a letter of authorisation for the person authorised to communicate on behalf of the Applicant - this should be printed, signed, scanned and saved as a pdf
a signed copy of Form A is required – please print, sign, and scan the signature pages to submit electronically
copy of previous MHRA Decision on Paediatric Investigation Plan or the EMA Decision/ PDCO opinion if the MHRA Decision is not available

Applicants do not need to complete a new version of the Template for UK Scientific Document.

All the proposed amendments to the PIP should be reflected in the modification template which is available to download from the PIP templates section of the PIP submission homepage.

For the list of and copies of literature references, the reference list should be in alphabetical order based on first author’s surname and year. References should be saved individually using the first author’s surname and year. This may be uploaded as a zip file containing all the individual references. Please only submit new references relating to this modification, not any previous references for the currently agreed PIP.

If relevant, and if have these have occurred / been amended since the current PIP was agreed, include the following in the supporting submission package:

copy of any Scientific Advice given by CHMP
copy of Scientific Advice given by MHRA
copy of Advice/Opinion/Decision given by competent authorities of other countries
copy of FDA written request
copy of Decision on Orphan Designation from regulatory bodies
Risk Management Plan
Investigator’s Brochure
Document Checklist

Do not include copies of the above if they were included in the currently or previous agreed PIPs.

Note that for Modification submissions, you will need to click the ‘List and copies of literature references’ button even though you may not have provided literature references as this is a mandatory field.

You should complete the online application on the MHRA Submissions homepage including the key elements section of the application, where all studies in the PIP must be provided irrespective of whether they are subject to the proposed amendments. If the modification to the agreed PIP is accepted, this information will be used to generate the new Provisional PIP decision. Therefore, please ensure where changes are not proposed to the PIP, you maintain the previous key elements as agreed in the currently agreed PIP. Where you propose amendments to the PIP in this request for a modification, the main features of these are specified in the key elements form, and the justification for these changes should be included in the request for modification form.

2.12.3 Guidance on completing the request for modification to an agreed PIP template

Applicants should download the ‘Template for request to modification of an agreed paediatric investigation plan’ 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. For each issue raised in the modification request, applicants should discuss the most appropriate route for addressing this; whether by modification of a key element, a deferral in initiation and/or completion of a study/ies, or requesting a waiver. An assessment of the effect of both making and failing to make the proposed change should be provided.

In Section 1 (Administrative information)

Fill in preceding procedure number (UK-PIP number)
If there is a corresponding agreed EU Paediatric Investigation Plan, please provide the EU-PIP number and EMA decision number (P/xxxx/yyyy)
If there is an agreed paediatric plan from another regulator, please include the details here

See guidance for applicants or companies with an agreed EU-PIP opinion given prior to the UK leaving the EU: https://www.gov.uk/guidance/procedures-for-uk-pips

Under ‘Information about the authorised medicinal product if applicable’

Indicate if the UK marketing authorisation has been obtained since the preceding procedure or it has been changed (such as variation, withdrawal) - full details must be added to the online application form Section A

In Section 2 (Reasons for applying) summarise the overall reason for the requested changes briefly in not more than one page. Include information such as

changes to development programme following regulatory interactions,
changes required due to recruitment difficulties
changes due to new clinical guidelines, standard of care

In Section 3 (List of proposed changes of measures and timelines):

Add rows and comment boxes as needed. Ensure a separate row for each key binding element is followed by a comment box. In case this is a new study, list all key binding elements and add “Study to be added”.

If the change regards the removal or addition of an entire study/measure, insert “Study to be added” or “Study to be deleted” together with a justification.

Only changes requested in this document will be considered by the MHRA. Include one table per study and list each key binding element that you wish to modify in a separate row. Do not include key elements you do not wish to change.

‘Preceding procedure’ is the latest agreed UK-PIP for which the UK decision was issued.

For each study in the agreed PIP, or for a new proposed study:

insert the study number and/or study identifier (as per preceding decision)
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, explain the proposed change(s)
change the key binding element as desired, where possible, highlight the change (for example using bold font, highlight, strike-through) but do not use track-changes
for each key binding element in the request for modification, include justification for change(s)
provide a concise and comprehensive explanation for each proposed change
additional information can be provided in a separate document only when necessary (for example including graphs or tables).

Save the template and upload as one of the supporting documents.

2.12.4 Procedural aspect for modifying an agreed PIP procedure

Refer to Section 2.9 for additional advice regarding procedural aspects of the submission.

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.

If the modification request is adopted as a positive proposed decision this will go on to replace the existing agreed PIP once the final decision has been issued as the legally binding document.

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. Applicants may request a withdrawal of the PIP modification request prior to issue of the Final Decision, and are also allowed to submit another request for modification at any time.

2.13 Decision

At the end of the procedure the licensing authority will either agree the proposed PIP and/or product specific waiver/ class waiver by adopting a positive decision, or a negative decision will be adopted where the application cannot be agreed. Applicants will receive a copy of the summary report along with a copy of the proposed decision letter on the PIP/ waiver, which will be uploaded by the Assessor to the relevant PIP application for applicants to download for their records.

Check the Documents carefully as, where the Decision is positive, it forms the basis for compliance checks, and any errors may delay marketing authorisation applications. If any errors are noticed or applicants would like to suggest minor edits to the text for clarity, please notify the MHRA as soon as possible so these can be discussed and rectified if necessary. Please edit proposed text changes directly in the decision Word document and use tracked changes.

If applicants accept the proposed decision

e-mail a confirmation by responding to the message sent directly from application via the MHRA PIP Communications mailbox or
if this has not been received, via the ukpip@mhra.gov.uk and use the MHRA PIP number in the subject line – ‘Decision MHRA-XXXXXX-PIPXX-XX’

Emails related to the applications are sent via the MHRA PIP Communications mailbox processmodel1958@mhrabpm.appiancloud.com. Please ensure the reply email is delivered to all recipients and saved in the correct case folder, please keep the subject line unchanged and always ‘reply to all’.

The messaging system cannot accept attachments in emails. If applicants wish to provide documents please upload them to the ‘Documents’ folder of the relevant case and notify the MHRA.

Applicants will be asked to confirm acceptance, or provide comments to the both the Provisional Decision and Summary reports, by a given date. Applicants may receive a reminder email if the deadline for receipt of a response has passed. If the proposed decision is accepted, or applicants do not reply within 28 calendar days of date the Provisional Decision is sent to you, this Decision will become definitive. Final Decision documents will be issued by the licensing authority, and a public version of the Decision will be published on the MHRA website. Applicants will receive a copy of the final decision via the relevant PIP/ Waiver or Modification application.

If applicants do not wish to accept the Provisional Decision, they have the right to make representations as outlined in Section 5 of this guidance (Right to representation [written or oral] concerning provisional outcomes). Alternatively, applicants may withdraw your application before the proposed decision becomes final, or at any stage earlier in the procedure. Applicants are allowed to submit a new application for the same medicinal product and same condition via with a new PIP, waiver, or modification submission. This would start the process again at day 0 with a different PIP number.

2.14 Confirmation of an indication is part of a condition

If applicants need to confirm whether an indication is part of a condition for an agreed PIP or waiver decision, please submit an email request to ukpip@mhra.gov.uk. Please use the e-mail subject heading ‘confirmation of inclusion of an indication within an agreed condition’ and include the completed ‘Template for UK Confirmation of Indication Letter’ along with the UK-PIP number and Decision number (or the EU-PIP number and decision number if the EU-PIP was agreed before exit date and has not been superseded by an MHRA Decision).

The MHRA will issue a confirmation letter which should be included with the UK-PIP Decision document in your MHRA Regulatory Application to fulfil the Paediatric Requirements.

Question 3

3.  Class waiver

Accepted Answer

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.
are intended for conditions that occur only in adult populations.
do not represent a significant therapeutic benefit over existing treatments for paediatric patients.

MHRA has adopted the current EU class waivers list as applicable to UK, although this may be subject to future updates.

The relevant EMA decision on class waivers for the medicinal product and condition agreed prior to 01 January 2021 should be quoted with marketing authorisation applications in the UK.

From 01 January 2021, applicants must request confirmation of the applicability of the licensing authority’s decision on class waiver from the MHRA. In principle, the MHRA will aim to accept a positive EMA opinion on a class waiver request, following a targeted MHRA assessment. This is an additional step to ensure paediatric requirements for a PIP or product specific waiver will not be required at the time of marketing authorisation, particularly in cases where interpretation of the class waiver applicability may be difficult or controversial.

If applicants have received a negative opinion on the applicability of a class waiver from the EMA for their medicinal product, the MHRA must be notified of this outcome. Applicants will be required to submit a full product specific waiver application in the UK, or a UK-PIP with a copy of the EMA opinion on the class waiver. If applicants subsequently have received an EMA positive opinion on the product specific waiver request, this may be taken into account in the UK’s assessment. Applicants should notify the MHRA of this, so we determine whether a targeted or full assessment is required.

3.1 Request for confirmation of the applicability of the licensing authority’s decision on class waivers

Applicants must request confirmation of the class waiver by completing a Waiver Application on the MHRA PIP Submission portal by completing the letter of intent and Section A of the application.

However, unlike the request for a full product specific waiver, the Scientific Document is not required. Please download and complete the ‘Template for request for confirmation of the applicability of the MHRA’s decision on the UK-class-waivers’ which is available to download from the PIP templates section of the MHRA PIP Submissions homepage. The completed document, along with the relevant supporting documentation, and an (optional) cover letter should be uploaded to the relevant online Waiver application.

The MHRA recommends applicants consider early interaction for confirmation of class waiver status, to ensure paediatric requirements are met. Applicants should also monitor EMA and MHRA updates on class waivers.

The MHRA recommend applicants consider the mechanism of action of their medicinal product, and the evidence whether the medicinal product may meet an unmet paediatric therapeutic need. A product falling under a class waiver, does not stop an applicant submitting a voluntary PIP. The confirmation of applicability request also considers whether there may paediatric unmet need for a product, even though it is covered under a class waiver.

If applicants have requested confirmation of class waiver from the licensing authority, the MHRA will review and provide a Decision confirming the applicability of the Class waiver to your product, following the timelines as notified on full submission of the application. Applicants will also be notified if there are other potential paediatric interests suggested by the licensing authority. If the class waiver is considered applicable to the product, the Decision document must be included with the relevant marketing authorisation application tiggering UK’s paediatric requirements.

Question 4

4.  Operation of the compliance check

Accepted Answer

This section should be read in conjunction with the guidance “Procedures for UK-PIPs” which outlines the compliance check process for applicants with an agreed EU-PIP and UK-PIP:

For marketing authorisation, extensions or variations which trigger the UK’s paediatric requirements, applicants need to demonstrate compliance with an agreed PIP, unless a deferral, a full product-specific waiver, or class waiver has been granted for the product. Compliance will be checked as part of validation for a UK Regulatory Application submission triggering the paediatric requirements.

A compliance check is the verification that some or all studies/measures agreed in a PIP have been conducted in accordance with the PIP decision, including compliance with the agreed timelines for completion of measures. A full compliance check is when compliance is performed for a fully completed PIP, on all measures. A partial compliance check will cover all those measures, within the condition(s) that cover the therapeutic indication(s) included in the UK Regulatory Application, for which initiation and/or completion have not been deferred, and also those measures which are deferred, but whose date of completion occurs before the date of submission of the UK 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 UK date of submission of the application.

The studies or other measures checked for compliance are those that are part of the condition covering an indication for which an application for marketing authorisation is made and that were to have been completed at the time of the submission. Where the scope of the application is exceptionally covered by more than one PIP, all concerned PIPs will be checked for compliance.

The compliance check will determine whether:

the documents submitted cover all subsets of the paediatric population
for applications falling within the scope of HMRs Regulation 50A(3), read with regulation 50A (1)(b) (applications for new indications, pharmaceutical forms and routes of administration), the documents submitted cover the existing and the new indications, pharmaceutical forms and routes of administration
all the measures in an agreed PIP have been carried out in accordance with the key elements specified in the decision approving the PIP

It should be noted that:

applications for marketing authorisation or variation will need to comply with each key element.
minor deviations from key elements should not affect compliance.
when conditional language such as ‘could’ or ‘such as’ is used in the Agency decision, compliance may be confirmed even if these measures were not followed as suggested.

It is recommended to request a compliance check well before submission of a Regulatory Application to prevent delays in validation of the procedure. Therefore, applicants are advised wherever possible to request compliance check by MHRA no later than two months prior to the planned submission of a UK Regulatory Application.

Sequential partial compliance checks may be requested for individual measures, or groups of measures, for example after non-clinical studies, then after the first paediatric clinical study. Early submission for compliance checks will allow time to apply for a modification if changes are needed and therefore prevent delays in marketing authorisation. Consideration should be given to the planned date of a UK marketing authorisation application, regardless of route, and the agreed dates of measures within the PIP.

In order to benefit from the Paediatric Rewards under HMRs regulation 58A; the MHRA will need to be satisfied that the material provided by the application pursuant to regulation 50A(3) demonstrates compliance with the agreed PIP.

4.1 Documents for compliance check

Applicants must submit as part of the submission package for a request for modification:

a completed copy of the ‘Template for cover letter UK-compliance check’ submitted as Word and PDF versions*
a letter of authorisation for the person authorised to communicate on behalf of the Applicant - this should be printed, signed, scanned and saved as a pdf, if this has not been provided previously in the previous MHRA procedure, or if this is first procedure related to an adopted UK-PIP
copy of previous MHRA Decision on Paediatric Investigation Plan or the EMA Decision/ PDCO opinion if this was an adopted UK-PIP not superseded by an MHRA Decision.

*Refer to guidance Procedures for UK-PIPs for further information regarding the need for a cover letter.

4.2 Procedure for compliance check

Applications for a compliance check should be made through the MHRA Submissions homepage, by selecting the relevant application types and completing in sequence, each section of the application.

Please see the separately published MHRA Submissions homepage user reference guidance for the procedure for requesting a compliance check, and the supporting documents required. (see section Purpose of guideline above for link) Once the compliance check application is fully submitted, it will be assigned to an Assessor who will review and validate the assessment. Automated timelines will be emailed to applicants on full submission and on validation of the application, and should be used as the planned date for outcome on the assessment. However, the assessor may contact applicants with updated timelines for the assessment, and may discuss if there are any issues with the submitted documents.

Applicants are encouraged to present a report outlining their compliance based on the date of marketing authorisation, extension or variation application.

For medicinal products that fall under the scope of HMRs Regulation 50A(3), read with regulation 50A (1)(a) or Regulation 50A(3), read with regulation 50A (1)(b):

the 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).

Additionally, for applications falling under Regulation 50A(3), read with regulation 50A (1)(b):

how each of the existing and new indications, pharmaceutical forms and routes of administration have been covered by the documents referred to in regulation 50A(3) or a waiver or deferral as described in regulation 50A(5).

The applicant should complete the Measure section of the online application, ensuring a separate row is used for each key binding element (such as one row for primary endpoints, next row for secondary endpoints). The section should include the applicant’s position on compliance with the key elements and, where submitted with the marketing authorisation application, provide a cross-reference for each key element of the PIP to the location in the relevant module (document name, section and page number) in the UK marketing authorisation application. If a PIP has been modified, the table should be based on the latest decision by the Agency. A separate word table can be included if there are character limitations or the number of rows in the online application is exceeded.

For a full or final compliance check, you must include all previous compliance check outcomes as part of the application.

Outcome of compliance check

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 compliance check.

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 decision with those of the completed study report. A rapid compliance check will be offered at the end of a positive modification agreement.

For a partial compliance check, the Assessor will send applicants:

a compliance report confirming the outcome of the partial compliance check.

For a fully completed PIP (Full or Final Compliance check application) you will receive

a compliance report and a licensing authority decision letter

For category 2 products under the Windsor Framework 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.

The licensing authority statement of compliance when all of the agreed PIP measures have been completed, will be issued, if appropriate, when a marketing authorisation application (initial, extension or variation) is granted.

See Procedures for UK-PIPs” for further guidance.

Question 5

5.  Right to representation (written or oral) concerning provisional outcomes

Accepted Answer

When a proposed decision (in relation to paediatric matters) is issued by the MHRA for applicant consideration, applicants have the right to inform the MHRA that they disagree with this provisional outcome. Applicants are allowed to request the opportunity to make written or oral representations to the Commission on Human Medicines, by informing the MHRA in writing within 28 days from the issuing date of the proposed decision (or such longer period as the licensing authority may allow). The authorised contact person should make their request to the Paediatric Team Manager at ukpip@mhra.gov.uk

The Paediatric Team will contact applicants to give information about the process for making representations, and MHRA will publish further advice in due course.

If no request to make representations is made, if a request is withdrawn, or if applicants make a request but fail to provide appropriate documentation, the proposed decision will become definitive via a final decision letter.

Question 6

6.  Annual report on deferrals

Accepted Answer

Marketing authorisation holders with an agreed UK-PIP who have received a deferral must submit annual reports to the MHRA. An annual report should be submitted for each PIP even if there are several PIPs for the same medicinal product. The first annual report should be submitted within the period of twelve months beginning with the date on which the licensing authority granted the deferral.

The annual report should update the MHRA on the progress of paediatric studies in relation to the agreed PIP decision and deferral. This information should be submitted via the MHRA Submissions homepage using the annual report page, navigating from the PIP homepage.

If there is a licensed paediatric indication the annual report submission should include details regarding the plans for placing the products on the market. This should be included in a separate document uploaded to Part 5 of the online application. Please refer to Section 10 (Placing products on the market) for additional information.

Once submitted, the MHRA will provide an acknowledgement notification usually within 6 months of the submission, unless one is requested from the MHRA earlier.

Question 7

7.  Notification of administrative changes

Accepted Answer

Communications about the procedures, and the summary reports and decision will be e-mailed to the authorised contact person. Therefore, please ensure this information is kept up to date.

If an applicant needs to make administrative changes to a UK-PIP procedure, please fill in the ‘Template for notification of change of the UK-paediatric investigation plan - waiver applicant – addressee’ available on the MHRA Submissions homepage available to download from the PIP templates section of the PIP tile homepage.

Submit electronically with the UK-PIP procedure number to: ukpip@mhra.gov.uk

This should be used to inform the MHRA of administrative changes such as a change of applicant where there is a new legal entity, a change of applicant’s particulars (where the legal entity remains unchanged), a change of authorised contact person, a change of contact point for public enquiries. Please select all the applicable changes required via the tick-boxes on the template.

For the purpose of this notification the:

“Applicant” is defined as a person/entity that applied for an (ongoing) paediatric procedure or the addressee of the UK decision (for finalised procedure).
“Authorised contact person” is a natural person, authorised by the ‘Applicant’ to communicate with the MHRA regarding the listed procedure.

Please insert the new or changed particular(s) for the applicant, authorised contact person, and/or contact point for public enquiries, or insert “N/A” where there is no change.

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.

Authorisation letter(s) must be enclosed with the notification

in case of the change of ‘Applicant’ due to takeover by different legal entity (tick-box 1); it is to be issued by the new legal entity to authorise the contact person; it must be issued to a name of a natural person who signs this notification on their behalf (authorisation letters to legal entities only cannot be accepted)
if the current authorised contact person is no longer available to sign the notification; it is to be issued by the current applicant to authorise the new contact person signing this notification on their behalf; it must be issued to a name of a natural person, authorisation letters to legal entities only cannot be accepted
confirmation of the change in legal entity should also be provided
a notification without the required authorisation letter(s) will not be processed by the MHRA.

The particulars listed in the notification will be updated only in the records or either the ongoing or the latest finalised UK-PIP/modification/waiver procedure.

Change of Applicant’s Name / Address will have no impact on procedural outcome documents, if already issued. The applicant’s name on the MHRA website will remain as per the UK decision.

Question 8

8.  Notification of discontinuation or suspension of a UK-paediatric development which is covered by an agreed UK-PIP or an EU-PIP Decision

Accepted Answer

For applicants with an agreed UK-PIP (or EU-PIP agreed before exit date), wishing to inform the MHRA of discontinuation or long-term suspension of the paediatric development for a specific condition, the ‘Template for notification of discontinuation of a UK-paediatric development which is covered by an agreed UK-PIP’ located in the MHRA Submissions homepage should be used. Please include details of:

active substance/s
invented name
the latest UK- or EU-PIP decision number
the corresponding UK- or EU-PIP number
the corresponding condition/s and indication/s
indicate whether discontinuation or suspension/long-term hold with possible re-start at a later date.
a description of the reason/s for discontinuation or suspension.
Please include the name and signature of the UK-PIP contact person, and the contact details for further information.

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

Question 9

9.  Publishing

Accepted Answer

The Regulatory Agency publishes the Decision on the initial UK-PIP, modifications and waivers via https://cms.mhra.gov.uk

A public version of the Decision with commercially sensitive information removed will be published usually within 3 months of finalisation of the procedure. A version of the public Decision is also provided to the applicant as a pdf document titled ‘MHRA-xxx…Final_Decision_Public’ on finalisation of the PIP procedure.

Compliance check assessments are not published.

Question 10

10.  Placing products on the market

Accepted Answer

Regulation 78A(4) (post-authorisation requirements in relation to UK marketing authorisations to which paediatric specific provisions apply), states that the holder of the UK marketing authorisation must place the product on the market taking account of the paediatric indication before the end of the period of two years beginning immediately after the day on which the paediatric indication is authorised. The timing of the product placement is based on the on the UK dates and approvals.

Products which fall under scope of this regulation are notified to the MHRA via the submission of a completed ‘Template for Appendix - Placing paediatric medicinal product on the UK market’ found in the PIP templates section of the PIP tile homepage. This should be included in the Annual report submission.

For products where the PIP is complete and there is no further obligation to submit the Annual Report, the completed template should be emailed to ukpip@mhra.gov.uk

Question 11

11.  Contact

Accepted Answer

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, please email our Customer Services Centre at info@mhra.gov.uk or call 020 3080 6000.

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Purpose of guidance

1. Definitions

Paediatric investigation plan (PIP)

Adopted PIP

Agreed PIP

Compliance check

Class Waiver

Waiver (Product specific)

Deferral

Condition

Paediatric Investigation Plan indication

Proposed indication

Key elements

Measure

Study

Extrapolation Plan or Study

Modelling and simulation study

MHRA Provisional Decision

MHRA Final Decision

Assessment

2. Format and content of applications for agreement on or modification of a paediatric investigation plan and requests for waivers and deferrals

2.1 General principles and format

2.1.1 Structure of format

2.1.2 MHRA Submissions and templates

2.1.3 Supporting information

2.1.4 Paediatric population

2.1.5 Coverage of application

2.1.6 Preparing the application

2.2 Section 1 (Online Section A) - Administrative and product information

2.2.1 Name or corporate name and address of the applicant and contact person

2.2.2 Name of the active substance

2.2.3 Type of product

2.2.4 Details of the medicinal product

2.2.5 Marketing authorisation status of the medicinal product

2.2.6 Advice from a regulatory authority relevant to development in the paediatric population

2.2.7 Orphan medicine status

2.2.8 Planned application for marketing authorisation/extension of marketing authorisation/variation

2.3 Section 2 (Scientific Document) – Overall development of the medicinal product

2.3.1 Section 2.1. Discussion on pharmacological rationale and mechanism of action

2.3.2 Section 2.2. Discussion on similarities and differences in the condition between populations

2.3.3 Section 2.3. Current methods of diagnosis, prevention or treatment in paediatric populations

2.3.4 Section 2.4. Significant therapeutic benefit and/or fulfilment of therapeutic needs

2.3.5 Section 2.5 UK-Paediatric investigation plan indication and selected paediatric subsets

2.3.6 Section 2.6 Summary of regulatory advice and/or network, expert, patient input

2.4 Section 3 (Scientific Document) - Applications for product-specific UK-waivers

2.4.1 Section 3.1. Overview of the UK-waiver request

2.4.2 Justification for a product-specific UK-waiver

2.4.2.1 Section 3.2. Applications based on the disease or condition not occurring in the specified paediatric subset

2.4.2.2 Section 3.3. Applications based on lack of significant therapeutic benefit.

2.4.2.3 Section 3.4 Applications based on a likely lack of safety or efficacy in part or all of the paediatric population

2.4.2.4 Conclusion

2.5 Section 4 (Scientific Document) - Proposed UK-paediatric investigation plan

2.5.1 Section 4.1. Quality

2.5.1.1 Section 4.1.1. Existing pharmaceutical forms

2.5.1.2 Section 4.1.2. Proposed pharmaceutical forms for paediatric use

2.5.1.3 Section 4.1.3. Justification of components

2.5.2 Section 4.2. Non-clinical aspects

2.5.2.1 Section 4.2.1. Existing non-clinical data

2.5.2.2 Section 4.2.2. Proposed non-clinical development

2.5.2.3 Section 4.2.3. Justification of overall strategy and juvenile safety studies

2.5.3 Section 4.3. Clinical aspects

2.5.3.1 Section 4.3.1. Existing clinical data and planned studies in adults

2.5.3.2 Section 4.3.2. Proposed clinical development

2.5.3.3 Extrapolation

2.5.3.4 Graphic overview of milestones and timelines

2.5.3.5 Strategy for paediatric dose selection and PK/PD evaluation

2.5.3.6 Modelling and simulation analyses supporting paediatric development

2.5.3.7 Proposed clinical studies

2.5.3.8 Section 4.3.4. Other studies proposed

2.5.3.9 Considerations for planned long-term follow-up

2.6 Section 5 (Scientific Document) - Request for UK-deferrals

2.7 Section 6 (Scientific Document) - References and Annexes

2.8 Key Elements Form

2.9 Procedural guidance for PIPs

2.10 Interim PIP

2.11 Request for Modification (RfM) of an initial PIP

2.12 Modification on an agreed/ adopted PIP

2.12.1 Request to modify an agreed PIP guidance

2.12.2 Documents for a request to modify an agreed PIP