Last updated: 6 February 2023
See history of updates below
This post is an attempt to provide basic information about paediatric investigation plans (PIPs) in the EU. The information provided is by no means exhaustive. Click on the ‘+’ sign next to each heading to access the information under each heading.
In the sections below, whilst links have been provided to various Articles from the Paediatric Regulation (EC) 1901/2006 as published, it is also important to refer to the current consolidated version of the Regulation in order to capture any changes since the regulation was first published.
| Date | Update(s) |
|---|---|
| 6 Feb 2023 | Section entitled Stepwise PIP (sPIP) Pilot added with relevant content. |
A paediatric investigation plan (PIP) is a development plan aimed at ensuring that the necessary data are obtained from studies in children in order to support the authorisation of a medicine for children. PIPs describe how a medicine should be studied in children, as well as waivers and deferrals.
The applicable legislation for PIPs is the Paediatric Regulation which is comprised of the following two regulations:
- Regulation (EC) No 1901/2006 of the European Parliament and of the Council of 12 December 2006 on medicinal products for paediatric use
- Regulation (EC) No 1902/2006 an amending regulation in which changes to the original text were introduced relating to decision procedures for the European Commission.
The Paediatric Regulation came into force in the European Union (EU) on 26 January 2007. Its objective is to improve the health of children in Europe by facilitating the development and availability of medicines for children from birth to 17 years of age.
Whilst Regulation (EC) No 1901/2006 entered into force on 26 January 2007, some articles of the regulation became applicable later on as detailed below:
| Article of Regulation (EC) 1901/2006 | Date article became applicable | Further information |
|---|---|---|
| Articles 30 and 31 | 26 July 2007 | From this date, Paediatric Use Marketing Authorisation (PUMA) applications became possible. |
| Article 7 | 26 July 2008 | From this date, marketing authorisation applications for new products were/are required to include/contain results of studies conducted in compliance with an agreed PIP unless a waiver or deferral has been granted. |
| Article 8 | 26 January 2009 | From this date, applications (for authorised products protected either by a supplementary protection certificate or by a patent which qualifies for the granting of a supplementary protection certificate) for a new indication, new route of administration or new pharmaceutical form were/are required to include the results of studies in compliance with an agreed PIP unless a waiver or deferral has been granted. |
Applications for the following have to include the results of studies as described in an agreed PIP, unless the medicine is exempt because of a deferral or waiver:
- Applications for a marketing authorisation under Article 6 of Directive 2001/83/EC for a medicinal product for human use which is not authorised in the European Union at the time of entry into force of Regulation (EC) No 1901/2006 have to comply with the requirements of Article 7 of Regulation (EC) No 1901/2006
- For medicinal products with a marketing authorisation (and protected by either a supplementary protection certificate or by a patent which qualifies for the granting of a supplementary protection certificate in line with Article 8 of Regulation (EC) No 1901/2006), applications for authorisation of the following have to comply with Article 7 of Regulation (EC) No 1901/2006):
- a new indication (variation)
- a new pharmaceutical form (line extension)
- a new route of administration (line extension)
Sections 2.3 and 2.4 on this page of theEMA website should help you to understand more about the meaning of a new indication or new pharmaceutical form.
Clarification concerning ‘not authorised’ in the European Union as stated in 1 above:
The following table should help you to understand whether a medicinal product is considered authorised or not authorised in the EU at the time of entry into force of Regulation (E) 1901/2006 and whether Article 7 or Article 8 of Regulation (EC) No 1901/2006 of will apply to an application (i.e. an application for an MAA, new indication, new pharmaceutical form or new route of administration).
| Do you hold a product marketing authorisation with the active substance in question, in the EU | Is the product protected by a supplementary protection certificate (SPC)/ qualifying patent for a SPC | Does the product include a new or known active substance? | Does the product have an orphan designation? | Is the medicinal product which is the subject of the application considered authorised in the EU at the time of entry into force of Regulation (EC) No 1901/2006 | Which article of Regulation (EC) No 1901/2006 shall apply to the application? |
|---|---|---|---|---|---|
| No | The product may or may not be protected by an SPC/qualifying patent for a SPC | Could be a new or known active substance | Product may or may not have an orphan designation | No | Article 7 |
| Yes | The product is protected by an SPC/qualifying patent for a SPC | Known active substance | Product may or may not have an orphan designation | Yes | Article 8 (+Article 7) shall apply to any regulatory application to add a new indication (via a variation), pharmaceutical form or route of administration (both of the latter are line extensions). In this case, the PIP or waiver decision shall cover the existing and any new indication, pharmaceutical form or route of administration of the medicinal product concerned by the Global Marketing Authorisation (GMA). |
When submitting a new standalone application, in order to determine whether a product is considered ‘authorised’ or ‘not authorised’ in the EU at the time of entry into force of Regulation (EC) No 1901/2006 and whether Article 7 or 8 applies, it is important to understand the following:
- The global marketing authorisation (GMA) concept, together with
- the notion of ‘same marketing authorisation holder’
The global marketing authorisation includes the initial authorisation and all variations and extensions thereof, as well as any additional strengths, pharmaceutical forms, administration routes or presentations authorised, through separate procedures and under a different name, granted to the marketing authorisation holder of the initial authorisation. For further clarification, refer to the notice to applicants, chapter 1, section 2.3. Thus, the global marketing authorisation concept applies to products belonging to the same marketing authorisation holder.
According to the Commission communication on the Community marketing authorisation procedures for medicinal products (98/C 299/03), applicants belonging to the same mother company or group of companies, or which are ‘licensees’, have to be considered as one.
Article 8 of Regulation (EC) 1901/2006, confirms that for medicinal products with a marketing authorisation which are protected either by a supplementary protection certificate or by a patent which qualifies for the granting of a supplementary protection certificate, applications for authorisation of the following require PIPs:
- a new indication (variation)
- a new pharmaceutical form (line extension)
- a new route of administration (line extension)
This means that a PIP is not normally required fo an application for a new strength or a new presentation of a product.
Yes, PIPs are applicable for applications made via all of the application routes listed below:
- National
- Mutual recognition procedure
- Decentralised procedure
- Centralised procedure
Yes, applicants can request scientific advice from EMA in preparation of a PIP. The advice is free of charge for questions relating to the development of paediatric medicines. Applicants can also follow up a PIP with scientific advice, for example on combined adult and paediatric development in light of the PIP requirements.
The EMA discourages applicants from submitting scientific advice and PIP applications in parallel.
According to Article 16 of Regulation (EC) No 1901/2006, applications should be submitted, unless duly justified, ‘not later than upon completion of the human pharmaco-kinetic (PK) studies’, as specified in Section 5.2.3 of Part 1 of Annex 1 of Directive 2001/83/EC (refer to the current consolidated version of this Directive).
Recital 10 (or preamble) of the Regulation (EC) No 1901/2006 states that paediatric investigation plans should be submitted early during product development, in time for studies to be conducted in the paediatric population, where appropriate, before marketing authorisation applications are submitted.
It is appropriate to set a deadline for the submission of a PIP in order to ensure early dialogue between the sponsor and the Paediatric Committee.
Essentially, the format and content of applications for agreement or modification of a PIP and requests for waivers and deferrals is as follows:
- Part A: Administrative and product information
- Part B: Overall development of the medicinal product including information on the conditions
- Part C: Applications for product specific waivers
- Part D: Paediatric investigation plan
- Part E: Applications for deferrals
- Part F: Annexes.
More detailed information and/or clarification in available in the following documents:
- the European Commission’s Guideline on the format and content of applications for agreement or modification of a paediatric investigation plan and requests for waivers or deferrals and concerning the operation of the compliance check and on criteria for assessing significant studies
- The EMAs Guidance on paediatric submissions via eSubmission Gateway and eSubmission Web Client details the documents required for each of the procedure types listed below:
- Paediatric investigation plan (PIP) and product specific waiver submissions
- Answers to PDCO requests for modification (RfM) (resubmission following clock-stop)
- Modification of an agreed PIP
- Compliance check request
As per Article 16 and Article 17 of Regulation (EC) 1901/2006, the time required for agreement of a PIP is as follows:
| No of days | Overall time required |
|---|---|
| Within 30 days following receipt of the request for agreement of a PIP, The EMA shall verify the validity of the request and prepare a summary report for the Paediatric Committee. | 30 days + extra time for the provision of any requested supplementary information |
| Following receipt of a proposed valid PIP in accordance with Article 15(2), the PDCO shall appoint a rapporteur and within 60 days adopt an opinion on whether proposed studies will ensure the generation of the necessary data and whether or not the expected therapeutic benefits justify the studies proposed. | 60 days + extension of up to a further 60 days if PDCO asks applicant to modify PIP + extra time until requested supplementary information has been provided |
The overall duration will depend on the duration of the clock stops, i.e. how fast the applicant responds to the PDCO’s requests.
Applicants need to provide their product’s research product identifier (RPI) to carry out new paediatric procedures.
Since 10 October 2021, The RPI is a mandatory field in the electronic application form for:
- paediatric investigation plans (PIPs),
- modifications of agreed PIPs, and
- requests for waivers.
Applicants can request an RPI for their product via EMA’s IRIS system, following the IRIS guide to registration.
EMA uses RPIs to improve the efficiency of its processes and create a single identifier for all pre-authorisation activities. The RPI replaces the previously-used unique product identifiers (UPIs).
More information is available on this page.
It is the paediatric committee (PDCO) that is responsible for assessing the content of paediatric investigation plans PIPs.
The PDCO is the European Medicines Agency’s (EMA) scientific committee responsible for activities on medicines for children and to support the development of such medicines in the European Union by providing scientific expertise and defining paediatric needs. It was established when the Paediatric Regulation came into force.
The Committee’s main role is to determine the studies that companies must carry out on children as part of paediatric investigation plans (PIPs). The PDCO replaced the Agency’s previous Paediatric Working Group.
The PDCO interacts with other Agency committees, particularly the Committee for Medicinal Products for Human Use (CHMP), the Pharmacovigilance Risk Assessment Committee (PRAC) and the Committee for Orphan Medicinal Products (COMP) on any matters related to the development of medicines for paediatric use.
You can find out more about the PDCO here.
A PIP modification may occur in the following two circumstances:
i) While a PIP is under assessment (Article 17(2))
Within the 60-day period following submission of a PIP to the EMA, the PDCO may request the applicant to propose modifications to the plan, in which case the time-limit for the adoption of the final opinion shall be extended for a maximum of 60 days. In such cases, the applicant or the Paediatric Committee may request an additional meeting during this period. The time-limit shall be suspended until such time as the supplementary information requested has been provided.
ii) Following the decision agreeing a PIP (Article 22)
Following the decision agreeing the PIP, the applicant may encounter difficulties with its implementation which may render the plan unworkable or no longer appropriate. In these circumstances, the applicant may:
- propose changes or
- request a deferral or a waiver,
based on detailed grounds, to the PDCO. This is defined as a modification.
It is important to note the following:
- It is not possible to change or add a new active substance via modification of an agreed PIP procedure. This requires submission of a separate PIP application.
- Changes to or addition of route of administration or pharmaceutical form are permitted.
Within 60 days, the Paediatric Committee shall review these changes or the request for a deferral or a waiver and adopt an opinion proposing their refusal or acceptance.
For some medicines, the PDCO may grant deferrals or waivers.
Deferrals (Articles 20 – 21)
Deferrals allow an applicant to delay development of a medicine in children until for example there is enough information to demonstrate its effectiveness and safety in adults.
Even when studies are deferred, the PIP will include details of the paediatric studies and their timelines.
Initiation and/or completion of measure(s) may be deferred. This means that:
- an applicant can submit a Regulatory Application for a condition(s) in adults even if the deferred measures in children are either not initiated or not completed (as relevant).
- studies in children can be initiated and/or completed after applying for a marketing authorisation for use in adults.
Waivers (Articles 11 – 14)
Waivers may be granted when development of a medicine in children is either not needed or is not appropriate e.g. for diseases that only affect the adult population.
The requirement to submit a PIP is waived for specific medicines (product-specific-waiver) or classes of medicines (Class waivers) 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.
Further information on:
Annual reports on deferrals
Marketing-authorisation holders that have received a deferral on a PIP are obliged to submit annual reports to the Agency. These reports should provide an update on progress with paediatric studies in accordance with the decision of the Agency agreeing the PIP and granting a deferral.
Annual reports for newly authorised medicines
- If an agreed PIP for a new medicine contains a deferral, the applicant must send the first annual report to the Agency in the month before the first anniversary of the date of marketing authorisation.
- There is no need to submit annual reports before the marketing authorisation is granted.
Annual reports for medicines other than newly authorised mediines
For medicines other than newly authorised medicines:
- if the PIP decision is agreed less than six months before the anniversary date of the first marketing authorisation granted in the European Economic Area, the marketing-authorisation holder should send the annual report in the month before the next anniversary of the date of the marketing authorisation;
- if the anniversary date occurs more than six months after the date of the PIP decision, the report should be sent in the month before the anniversary date.
More information on the requirements for companies is available here.
The following table details many of the steps following the submission of a PIP to the EMA for assessment. Note that not all steps will apply to all applications.
| Step | Detail | Further information |
|---|---|---|
| Application for PIP or waiver or request for deferral is submitted | PIP or waiver is submitted with a request for agreement. A request may also be made at the same time, for deferral of the initiation or completion of some or all of the measures set out in that plan. Article 20(1) | |
| Validity of the request is verified | Within 30 days following the submission of a request for agreement of PIP or waiver, EMA verifies the validity the request and prepares a summary report for the PDCO. Article 16(2) | If appropriate, the EMA asks the applicant for additional particulars/documents and the 30 day time limit is suspended until these have been provided. Article 16(3). |
| A rapporteur is appointed and an opinion on the PIP is adopted as well as whether the initiation and/or completion of some or all of the measures in the PIP should be deferred. | Following receipt of a valid PIP, the PDCO appoints rapporteur and within 60 days, PDCO adopts an opinion on the PIP i.e. +ve or -ve. Article 17(1) At the same time as the PDCO adopts a +ve opinion under Article 17(1), it shall, of its own motion or following a request submitted by the applicant under Article 20, adopt an opinion (provided that the specified conditions are met), in favour of deferring the initiation or completion of some or all of the measures in the paediatric investigation plan. An opinion in favour of a deferral shall specify the time-limits for initiating or completing the measures concerned. (Article 21(1) | Within these 60 days, the PDCO may ask applicant to propose modifications to PIP, and extend the 60 day time-limit for a final opinion by a max of another 60 days. (Article 17(2)). In this case, the time- limit shall be suspended until the requested supplementary information has been provided. |
| EMA transmits opinion to the aplicant. | Within 10 days of receipt of the PDCO opinion, the EMA transmits it to the applicant. Article 25(1) | |
| Applicant may submit a request for re-examination | Within 30 days following receipt of PDCO opinion, the applicant may submit a written request to the EMA citing detailed grounds for a re-examination of the opinion. Article 25(2) | If, the applicant does not request re-examination within the 30-day period, the opinion of the Paediatric Committee shall become definitive. (Article 25(4)) |
| PDCO will appoint a new rapportuer and issue a new opinion. | Within 30 days following receipt of a request for re-examination, the PDCO having appointed a new rapporteur shall issue a new opinion confirming or revising the previous opinion. Article 25(3) | During this 30 day period, the rapporteur shall: · be able to question the applicant directly · inform the PDCO without delay in writing about details of contacts with the applicant. The opinion shall be duly reasoned and a statement of reasons for the conclusion reached shall be annexed to the new opinion, which shall become definitive. |
| The EMA adopts a definitive decision. | Within a period not exceeding 10 days following receipt of the PDCOs definitive opinion, the Agency adopts a decision. Article 25(5) | This decision shall be communicated to the applicant in writing and the definitive opinion of the PDCO shall be annexed to it. Article 25(5) |
| In the case of a class waiver, the EMA shall adopt a decision within 10 days following receipt of the opinion of the PDCO. This decision shall annex the opinion of the PDCO. (Article 25(6)) |
The Agency makes all opinions and decisions on PIPs, deferrals and waivers public, after deletion of information of a commercially confidential nature.
Yes, applicants must follow agreed PIPs exactly. Once the plan is complete, the European Medicines Agency or the medicines authorities in Member States check that companies comply with the agreed measures listed in each PIP.
These checks are necessary before the applicant can apply either for a marketing authorisation or a change to an existing marketing authorisation.
- Applicants can request a PIP compliance check to be performed prior to submitting a marketing-authorisation application.
- Alternatively, a compliance check will be carried out as part of the validation of the application.
- Applicants are strongly recommended to apply for the compliance check before submission of the marketing-authorisation application in order not to delay the validation phase.
- This check verifies that all the measures mentioned in the PIP decision, including the timelines for the conduct of the studies or collection of the data, have been completed in accordance with the key elements specified in the PIP decision.
Further detailed information on compliance checks is available:
- on this page on the EMAs website under the heading ‘Checking compliance’
- in this document entitled Questions and answers on the procedure of PIP compliance verification at EMA, and on paediatric rewards
- in the European Commission’s Guideline on the format and content of applications for agreement or modification of a paediatric investigation plan and requests for waivers or deferrals and concerning the operation of the compliance check and on criteria for assessing significant studies
Yes, joint guidance is available from the EMA and the US (FDA) for medicine developers submitting a PIP to EMA and an initial pediatric study plan (iPSP) to the FDA on the use of a cancer medicine in children.
- The purpose of the guidance is to speed up the development and authorisation of cancer medicines for children, given the rarity of childhood cancers.
- It describes the information that the two regulators typically require for their evaluations, to support:
- simultaneous submission to both regulators;
- coordinated discussions between the regulators in the context of ‘cluster activities’ on paediatric medicines;
- international collaboration in the design and conduct of clinical trials.
| Type of Medicinal product | Obligation concerning PIPs | Incentive(s) | Other information |
|---|---|---|---|
| 1) New medicines which may or may not have a new active substance 2) Already registered medicines for which one of the following is sought: · New indication · New pharmaceutical form or · New route of administration The above concerns medicinal products covered by Article 7 or Article 8 of Regulation (EC) No 1901/2006. | One of the following should be included with the marketing authorisation application: · the decision of the agency agreeing to the PIP + the results of all studies performed and details of all information collected in compliance with an agreed PIP · a product specific or class waiver · a deferral | A 6 month extension of the supplementary protection certificate (SPC), for the medicinal products that are covered by a SPC or a patent qualifying for a SPC. The above only applies upon the inclusion in a marketing authorisation of the statement referred to in Article 28(3). | This incentive shall also apply where completion of the agreed PIP fails to lead to the authorisation of a paediatric indication, but the results of the studies conducted are reflected in the Summary of Product Characteristics and, if appropriate, in the package leaflet of the medicinal product concerned. |
| Medicinal products that are orphan designated | A marketing authorisation application for such products should include the the results of all studies conducted in compliance with an agreed PIP, | In line with Article 37, provided that the statement referred to in Article 28(3) is subsequently included in the marketing authorisation granted, the 10 year period referred to in Article 8(1) of Regulation (EC) No 141/2000 shall be extended to 12 years i.e. a 2 year extension of the market exclusivity. | |
Paediatric-use marketing authorisation (PUMA) Already authorised medicines that are not protected by a patent or supplementary protection certificate (i.e. off-patent medicines) being developed specifically for use in children are eligible for a PUMA. | A PUMA application has to contain the results of all studies performed and details of all information collected in compliance with an agreed (PIP). The following must be included in Module 1.10 of the application dossier · The corresponding EMA decision · the PDCO opinion on compliance or the applicant’s compliance report | If a PUMA is granted, the product will benefit from 10 years of market protection as an incentive. This includes an 8-year period of data exclusivity, and a 10 year period of market exclusivity, preventing generic applications from relying on the dossier of the reference product or placing the product on the market. |
On this page, you can view reports on MA holders benefitting from rewards and incentives.
A focus group comprising representatives of the pharmaceutical industry, EMA, as well as members of the PDCO, has developed a framework for a “stepwise PIP” (sPIP) concept, i.e. a leaner regulatory-scientific approach in agreeing a PIP that allows for changes to be made to PIPs as more evidence becomes available over time1.
- This will allow, in selected cases, to leave some elements of a PIP open to further refinement after first agreement, with a commitment to fill the gaps once certain milestones are reached, and necessary scientific evidence becomes available.
- Additionally, the key elements to be specified in PIP opinions have been revised in order to focus only on essential elements at an appropriate level of detail.
- The PIP summary report template has been revised along the same lines and is planned to be published in the near future.
- In addition, administrative submission requirements for PIP applications and procedural aspects of the PIP compliance check have been simplified.
- Exploring the feasibility of these new approaches and further finetuning is planned during a pilot phase to start in February 2023.
More information on this newly developed framework launched on 6 February 2023, is provided in the published document entitled Guidance for Stepwise PIP pilot.
The sPIP concept will be piloted starting in Q1 2023 with 8 sPIP adopted initial opinions in order to gather experience to shape the process accordingly and to inform decision making on its use in the future.
1Report entitled Boosting the development of medicines for children: closing report of the EMA and European Commission (EC) action plan on paediatrics (6 February 2023)
Detailed guidance
Here, you can find detailed guidance for companies intending to apply for a paediatric investigation plan (PIP), waiver, deferral or product-specific waiver, as well as for companies that already have an agreed PIP.
More information on paediatric requirements
You can find more information on paediatric requirements for: