Pediatric Investigation Plan Explained

You need a PIP (or an EMA waiver in its place) whenever you plan an EU marketing authorisation application for a medicine not yet authorised in the EU. You also need one for a new indication, pharmaceutical form or route of administration of an authorised product that is still protected by an SPC or an SPC-qualifying patent. The plan has to be submitted early: "not later than upon completion of the human pharmaco-kinetic studies in adults" (EMA Procedural advice on paediatric applications, EMA/672643/2017 Rev. 15, 15 April 2026, section 6.1, quoting Article 16 of Regulation (EC) No 1901/2006).

1. Applications that trigger the requirement

Situation	Paediatric Regulation provision	What the application must include
New medicine (not authorised in the EU on 26 July 2008)	Article 7	Results from the agreed PIP; or a PIP decision granting a deferral; or a product-specific waiver; or a class waiver (EMA procedural advice, section 1)
Authorised product protected by an SPC (Regulation (EC) No 469/2009) or by a patent that qualifies for an SPC, when the application is for a new indication, new pharmaceutical form or new route	Article 8	The same: PIP decision or waiver decision [2][3]
Paediatric-use marketing authorisation (PUMA) for an off-patent product	Article 30	PIP decision number [4]

The "global marketing authorisation" concept and the "same marketing authorisation holder" notion decide whether a product counts as already authorised in the EU (EMA procedural advice, section 1).

2. Applications that don't need one

• Generics (Art 10(1) of Directive 2001/83/EC), hybrids (Art 10(3)), biosimilars (Art 10(4)) and well-established use (Art 10a) are exempt (EMA procedural advice, sections 1, 3-4).
• The centralised application form also says the paediatric sections do not apply to traditional herbal medicinal products ^[5].
• The variation form says Article 8 does not apply when the product has no SPC or SPC-qualifying patent ^[3].

3. When to submit

• Article 16 requires the PIP or waiver request to be submitted, "except in duly justified cases", by the time the adult PK studies (Annex I, Part I, Section 5.2.3 of Directive 2001/83/EC) are complete.
• In practice, EMA says submission should come no later than the end of healthy-subject or patient PK, or the start of adult phase II (proof-of-concept). It "cannot be after initiation of pivotal trials or confirmatory (phase-III) trials".
• EMA welcomes earlier submission, even before the first adult PK studies. A PIP for a new active substance submitted during phase III, or after trials in children have started, "is likely to be considered unjustified" (section 6.1).

4. Planning for the compliance check

• PIP compliance checks "must be carried out prior to marketing authorisation/variation/extension of marketing authorisation" (section 5.1).
• Submission deadlines follow the PDCO meeting calendar (section 5.1).
• EMA offers pre-submission advice. Requests should go in, "preferably two months prior to the intended submission date" (section 5.2.2).
• A copy of the PIP or waiver decision goes in Module 1.10 of the application ^[6].

5. Waivers and deferrals in place of the full plan

• A deferral lets paediatric measures follow the adult studies.
• A product-specific waiver (full or partial) removes the obligation for some or all paediatric subsets.
• If your product falls under EMA's class waiver list, you can ask EMA to confirm it applies. EMA replies in about two months; if it doesn't apply, you then need a product-specific waiver or a PIP (sections 4.1, 6.3).

Approach: I checked the EU Notice to Applicants (Volume 2) application forms and the chapter on paediatric requirements, then EMA's current procedural advice on paediatric applications and its PIP page. The Paediatric Regulation itself is not in the datasets I can search, so the article wording above is as EMA quotes it.

Sources:

• EMA, Procedural advice on paediatric applications (EMA/672643/2017 Rev. 15)
• EMA, Paediatric investigation plans

The UK copies the EU PIP system almost exactly: since 31 December 2020 the Human Medicines Regulations 2012 require an MHRA-agreed UK PIP (or a waiver or deferral), with the same triggers, timing and SPC-extension reward. The US works differently. Paediatric studies are required under PREA, without the EU/UK patent or SPC condition and with an exemption for orphan indications. The reward comes from a separate, voluntary programme, BPCA, which gives 6 months of pediatric exclusivity for studies FDA asks for in a Written Request.

United Kingdom (MHRA)

• Legal basis: Regs 50A-50J were inserted into the Human Medicines Regulations 2012 from 31 December 2020 by S.I. 2019/775 ^[7].
• What triggers it:
  • an initial UK marketing authorisation for a relevant medicinal product; or
  • a new indication, pharmaceutical form or route for an authorised product, but only if the product is protected in the UK by an SPC or an SPC-qualifying patent ^[7].
• What the application must contain: "the results of all studies performed... in compliance with an agreed paediatric investigation plan", unless a deferral (reg 50C) or waiver (reg 50D) has been granted or one of regs 51-54 applies ^[7].
• When to submit: "not later than upon completion of the human pharmaco-kinetic studies in adults", unless the MHRA agrees to a later request ^[8]. This is the same as the EU.
• Waiver grounds: the product is likely to be ineffective or unsafe in children; the condition occurs only in adults; or there is no significant therapeutic benefit. The MHRA must publish a list of class waivers ^[9].
• Rewards:
  • a 6-month SPC extension where the authorisation includes the compliance statement;
  • for orphan authorisations, the orphan reward in reg 58D(5) applies instead;
  • a paediatric-use marketing authorisation (PUMA) gets data and marketing exclusivity ^[10][11].
• Obligations after approval:
  • place the product on the market with the paediatric indication within 2 years;
  • submit results of paediatric studies the MAH sponsors within 6 months of the study ending;
  • send annual deferral reports, the first within 12 months of the deferral ^[12].
• What it means for an EU-first programme:
  • An EU PIP does not replace a UK PIP. MHRA guidance says plans agreed by other regulators "cannot be used to validate an MHRA regulatory application", but where an EU PIP exists the MHRA does a targeted assessment.
  • The compliance check request "must be submitted no later than 2 months prior to" the triggering submission (MHRA, Procedures for UK PIPs).
  • For Northern Ireland (Category 2 UK authorisations), the EU PIP obligations under the Paediatric Regulation still apply ^[7].

United States (FDA)

Point	US position	Difference from EU/UK
Mandatory studies (PREA, 21 CFR 314.55)	Applications for a "new active ingredient, new indication, new dosage form, new dosing regimen, or new route of administration shall contain data that are adequate to assess the safety and effectiveness... in all relevant pediatric subpopulations" [13]	Also covers a new dosing regimen. There is no patent/SPC condition in the text.
Extrapolation	FDA "may conclude that pediatric effectiveness can be extrapolated" from adult studies where the disease and drug effects are similar enough [13]	Written into the regulation itself
Deferral	Possible until after adult approval. A deferral request must include a certification of the grounds, the planned studies, and evidence of due diligence [13]	Similar idea; deferred studies become tracked postmarketing requirements
Waiver	Full or partial waiver if: no meaningful therapeutic benefit and not likely to be used in a substantial number of children; studies impossible or highly impractical; or evidence the product is ineffective or unsafe. A partial waiver is also possible where attempts to make a pediatric formulation have failed [13]	Grounds are framed differently and include feasibility of the studies and formulation failure
Orphan indications	"This section does not apply to any drug for an indication or indications for which orphan designation has been granted" [13]	UK reg 50A has no orphan exemption from the PIP; orphans instead get a different reward (reg 58D(5))
Plan document	The initial Pediatric Study Plan (iPSP) under FD&C Act section 505B(e), covered by FDA's final guidance of July 2020 (FDA iPSP guidance)	The guidance page says it covers timing, but I couldn't open the guidance text, so the iPSP deadline isn't confirmed here
Reward	None under PREA. Under BPCA (section 505A), studies done to an FDA Written Request earn 6 months of exclusivity. It "attaches to the END of all existing marketing exclusivity and patent periods" for all of the applicant's products with the same active moiety, and is "not tied to approval of labeling". The studies are voluntary (FDA, Pediatric exclusivity FAQ)	In the EU/UK the reward is tied to complying with the mandatory plan and adds to the SPC. In the US the exclusivity is a separate, voluntary track.
Enforcement	Deferred PREA studies are listed as postmarketing requirements. For example, rifaximin PMR 858-1 got an FDA noncompliance letter and a refused deferral extension [14]. The same requirements also apply to biologics: PMR 125814/0-2 for CAPVAXIVE has been fulfilled [15]	Comparable to UK annual reports and compliance listing (reg 58B) [16]

In practice you need three separate paediatric agreements: an EU PIP, a UK PIP (with a targeted MHRA review if the EU PIP exists) and an FDA iPSP. If you want US exclusivity, get the Written Request before you submit the studies: FDA says it will not grant exclusivity for studies "submitted to the Agency before the Written Request is issued" (FDA PREA page).

Approach: I used the UK Human Medicines Regulations 2012, 21 CFR Part 314 and FDA's postmarketing requirements database, plus MHRA and FDA guidance pages. The PREA and BPCA statutes themselves are not in the datasets, and FDA's guidance PDFs (including the iPSP guidance) could not be opened.

Sources:

• MHRA, Procedures for UK paediatric investigation plans
• FDA, Pediatric Research Equity Act
• FDA, Qualifying for Pediatric Exclusivity under Section 505A (FAQ)
• FDA, iPSP guidance page (July 2020)