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Explainermoderate confidence 3 of 5: One strong study, or several smaller consistent ones.Q8-impact

The EU paediatric investigation plan: an obligation, not an incentive - and the deferral is the loophole

also called PIP · paediatric investigation plan · Paediatric Regulation · Regulation (EC) No 1901/2006 · PDCO · class waiver

Unlike the American programmes, Europe does not bribe companies to study drugs in children - it requires them to, as a condition of selling the drug to adults. The catch is that the requirement can be waived for diseases children do not get, or deferred so the adult launch goes ahead years before any child is dosed.

The same thing, for a scientist

Regulation (EC) No 1901/2006 makes a paediatric investigation plan a condition of validity for a marketing authorisation application for a new active substance, and for new indications, forms or routes of an authorised product still under patent or SPC (Article 7). The plan is agreed by the Paediatric Committee (PDCO) and must be submitted no later than on completion of adult pharmacokinetic studies (Article 16(1)). Two escape routes exist: a waiver where the product is likely unsafe or ineffective in children, lacks significant therapeutic benefit, or the condition occurs only in adults (Article 11(1)) - operationalised through a class waiver list last revised on 2 June 2025 - and a deferral where adult studies must precede paediatric work (Article 20(1)). Compliance is rewarded by a six-month supplementary protection certificate extension (Article 36(1)) or, for an orphan medicinal product, extension of the ten-year EU market exclusivity to twelve years (Article 37). Acute leukaemia is not class-waived. Revumenib holds EU orphan designation EU/3/21/2569 (2022-01-14) but, as of 2026-09-18, no EU marketing authorisation and no published PIP decision number could be located; the same is true of ziftomenib. This node's KMT2A-specific findings are partial and the negative results rest on searches that EMA's bot filter degraded.

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Why this is an obligation, not an incentive

This is the structural difference from the US stack and it is worth stating first. Orphan designation, the rare paediatric disease voucher and breakthrough designation are all carrots: a sponsor is free to ignore them. The EU Paediatric Regulation is a gate.

Under Article 7 of Regulation (EC) No 1901/2006, a marketing authorisation application for a new medicinal product is not valid unless it includes one of: the results of all studies performed in compliance with an agreed paediatric investigation plan; a decision granting a product-specific waiver; confirmation that the product falls under a class waiver; or a decision granting a deferral 1. The same obligation attaches under Article 8 to new indications, new pharmaceutical forms and new routes of administration for already-authorised products still covered by a patent or SPC.

The plan is agreed by the Paediatric Committee (PDCO), which issues opinions and can attach deferrals and waivers; PDCO also gives free scientific advice on paediatric questions 2. Article 16(1) requires the PIP to be submitted no later than on completion of adult human pharmacokinetic studies - that is, early, before phase 2 is done 1.

Effect on a KMT2A programme: a sponsor cannot reach the EU adult market with a new menin inhibitor without having engaged PDCO on children first. That is a real and underappreciated difference from the US, where PREA's paediatric assessment can be, and for revumenib under 1 year of age was, waived at approval.

The two escape routes: waivers and deferrals

Waivers (Article 11(1)). PDCO may waive the paediatric obligation where the product is likely to be ineffective or unsafe in part or all of the paediatric population, where the condition occurs only in adult populations, or where the product does not represent a significant therapeutic benefit over existing paediatric treatments 1.

The Article 11 ground is operationalised through a class waiver list: a standing EMA decision naming classes of medicines for which no PIP need be submitted at all. EMA's current list was updated on 2 June 2025, and it supersedes previous class waiver decisions. It is heavily oncological - malignant neoplasms of the breast, prostate, lung, intestinal and gynaecological sites are on it, alongside non-oncology adult conditions such as Alzheimer's disease and age-related macular degeneration 3.

Acute leukaemia is not on that list. A menin inhibitor developed for acute leukaemia cannot be class-waived out of paediatric development in the EU. This is the single most important regulatory fact in this node and it works in children's favour.

Deferrals (Article 20(1)). PDCO may defer initiation or completion of some or all PIP measures where it is appropriate to conduct adult studies first, or where paediatric studies will take longer 1. A deferral does not remove the obligation; it moves it past the adult authorisation. This is the mechanism by which an adult drug reaches the market years before any child is dosed, and it does so entirely lawfully.

What compliance is worth

The Regulation pays for compliance in patent-life currency, and the two rewards are alternatives rather than a stack:

  • Article 36(1) - where an application under Article 7 or 8 includes the results of all studies conducted in compliance with an agreed PIP, the holder of the patent or supplementary protection certificate is entitled to a six-month extension of the SPC 4.
  • Article 37 - where the product is a designated orphan medicinal product and the application includes all agreed PIP study results, the ten-year market exclusivity under Article 8(1) of Regulation (EC) No 141/2000 is extended to twelve years 4.

For an orphan menin inhibitor in the EU, the operative reward is therefore +2 years of market exclusivity, not +6 months of SPC. Revumenib already holds EU orphan designation (EU/3/21/2569, granted to Syndax Europe B.V. on 2022-01-14 for acute myeloid leukaemia) 5, so if it is eventually authorised in the EU with a completed PIP, the Article 37 reward is the one in play: exclusivity to 12 years from authorisation.

Note the interaction with the US picture. The Article 37 reward is contingent on completing the PIP - including, in principle, the paediatric measures. That is a materially stronger link between dosing children and being paid than anything in the US stack, where the rare paediatric disease voucher is awarded on an approval event and the orphan tax credit is proportional to spend.

What is actually on file for the menin inhibitors in the EU, as of 2026-09-18

Verified. The European Commission granted orphan designation EU/3/21/2569 for the treatment of acute myeloid leukaemia to Syndax Europe B.V. on 14 January 2022, for the active substance corresponding to revumenib; the EMA record describes the mechanism as disrupting the KMT2A-menin interaction 5.

Not found, despite looking.

  • No EU marketing authorisation or EPAR for Revuforj / revumenib. The expected EPAR path returns 404, and trade commentary in 2026 still framed EU approval as a future event rather than a completed one 6.
  • No published PIP decision number (the EMEA-XXXXXX-PIPNN-YY form) could be located for revumenib or for ziftomenib.
  • No EU marketing authorisation or orphan designation located for ziftomenib.

How hard this negative is: not very. EMA's public search endpoints returned HTTP 401 security-verification pages to every automated request made for this node, and EMA's own orphan designation record for revumenib does not contain the string "revumenib" - it names the substance by full IUPAC chemical name. A PIP decision for revumenib could exist and not have surfaced. These are absence-of-retrieval findings, not absence-of-record findings, and they are recorded here so that the next person does not repeat the search believing it was conclusive.

The one thing that is safe to say: as of 2026-09-18 no menin inhibitor is authorised for marketing in the European Union for any indication, which means no European child with KMT2A-rearranged leukaemia has routine access to a menin inhibitor outside a trial or a national compassionate-use scheme - roughly two years after the US approval.

Facts and figures
programmeEU paediatric investigation plan
jurisdictionEU
legal basisRegulation (EC) No 1901/2006
is requirement not incentivetrue
obligation article7
waiver article11(1)
submission timing article16(1)
deferral article20(1)
spc extension months6
spc extension article36(1)
orphan exclusivity years base10
orphan exclusivity years with pip12
orphan reward article37
class waiver list last updated2025-06-02
acute leukaemia class waivedfalse
revumenib eu orphan designationEU/3/21/2569
revumenib eu orphan designation date2022-01-14
revumenib eu marketing authorisation foundfalse
revumenib pip decision number foundfalse
ziftomenib eu marketing authorisation foundfalse
ziftomenib pip decision number foundfalse
any menin inhibitor authorised in eufalse
used for kmt2apartial
as of2026-09-18
How this could bite us back
  • The deferral is the loophole, and it is used as designed. Article 20 lets PDCO postpone paediatric measures so that adult authorisation is not delayed. The legal effect is that a company satisfies a paediatric obligation with a promise, launches into the adult market, and dose the first child years later. Nothing about that is an abuse - it is the statute working. It simply means that in Europe, as in the United States, the adult market sets the clock and children are scheduled around it.
  • The class waiver is a stronger version of the same problem and it has an evidentiary track record. Pearson and colleagues examined 147 oncology class waivers covering 89 drugs and found that 54% of those drugs had a mechanism of action that warranted paediatric development. Waivers are granted on the indication - where the adult tumour is - not on the target, and paediatric cancers are driven by the same targets under different histologies. A menin inhibitor is safe from this because acute leukaemia is not class-waived; a drug hitting the same chromatin complex in an adult-only solid tumour would not be.
  • The rewards are patent-life instruments, which means their value scales with the size of the adult market the patent protects, not with the number of children studied. Six months of SPC on a blockbuster is worth hundreds of millions; six months on a drug whose entire indication is a few hundred patients a year is worth very little. The Paediatric Regulation pays most to sponsors who need the least persuading, and pays almost nothing where the paediatric population is the whole market.
  • For an orphan product the reward is +2 years of market exclusivity (Article 37) rather than the SPC extension - which means the sponsor is paid for paediatric compliance in the currency of a longer monopoly over the very children's drug in question. A European family gains access two years later to a generic of the drug their child's paediatric data helped establish. The reward and the harm land on the same population.
  • Two years after US approval, as of 2026-09-18 no menin inhibitor is authorised anywhere in the European Union. A regulatory framework that makes paediatric study a condition of market entry also makes market entry slower, and the children who pay for that delay are not the ones in the trials - they are the European children who cannot get the drug at all. This is the honest cost of the obligation model and it should not be papered over when comparing it favourably to the US carrot model.
  • Compare the two regimes on the specific question of infants. FDA approved revumenib for children aged 1 and over and formally waived the study requirement below 1 year as impossible - for a lesion that defines infant leukaemia. Europe has not yet authorised the drug at all. Neither system has produced a dosed, labelled, licensed therapy for an infant under 1 year old with KMT2A-rearranged leukaemia. One did it by exempting them; the other by not arriving. The outcome for the child is identical.
Still open
  1. Does a PIP decision exist for revumenib, and if so what is its EMEA-XXXXXX-PIPNN-YY number, what age groups does it cover, and does it carry a deferral? EMA's public search blocked automated retrieval; this needs a manual check of the EMA PIP register.
  2. Has a marketing authorisation application for revumenib been submitted to EMA, and is it on the medicines-under-evaluation list? A CHMP opinion would be the first public signal.
  3. Does the 2 June 2025 class waiver list touch any leukaemia entity at all? The list was read by automated summary only; the annex should be read verbatim.
  4. If revumenib is eventually authorised in the EU as an orphan medicinal product with a completed PIP, does the Article 37 twelve-year exclusivity actually require paediatric measures in infants under 1 year, or can PDCO accept a lower age bound as the US did?
Every source behind this entry (8)
  1. E1established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.database

    Regulation (EC) No 1901/2006 Article 7 conditions a marketing authorisation application on agreed PIP results, a waiver, a class waiver or a deferral; Article 11(1) sets the waiver grounds including that the condition occurs only in adult populations; Article 16(1) requires PIP submission on completion of adult pharmacokinetic studies; Article 20(1) permits deferral where adult studies should precede paediatric studies.

    Regulation (EC) No 1901/2006 of the European Parliament and of the Council of 12 December 2006 on medicinal products for paediatric use · European Parliament and Council of the European Union · Official Journal of the European Union, L 378/1 2006
    What this evidence cannot show

    Article content summarised from the consolidated EUR-Lex text via automated extraction; Article 7 and 11 content is paraphrased rather than quoted. The Regulation has been amended since 2006 and is under review as part of the EU pharmaceutical package.

    Evidence that argues against this (1)
    • Direct measurement of whether the Regulation delivers paediatric oncology medicines, and the answer is mostly no. A cross-sectional analysis of every onco-haematological medicine authorised by EMA since 2016 found 48 such drugs, of which only 7 (15%) had a paediatric indication; 2 (4%) had paediatric information in the SmPC without an indication; and 41 (85%) had no reference to the paediatric population in the SmPC at all. Seventeen of the 48 (35%) had no PIP, and 11 had been granted a waiver from presenting paediatric study results; the remaining 19 active ingredients carried 28 PIPs between them. The authors' own conclusion is that 'PIPs represent an opportunity, but demand for the paediatric population is still huge.' Abstract read via PubMed; full text not read. Lasala R et al. 2021
  2. E2established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.database

    EMA states that all applications for marketing authorisation for new medicines must include the results of studies described in an agreed paediatric investigation plan unless exempt by deferral or waiver, and that the Paediatric Committee evaluates PIP applications, issues opinions and may grant deferrals or waivers.

    Paediatric investigation plans · European Medicines Agency · EMA human regulatory overview 2026
    What this evidence cannot show

    Retrieved 2026-09-18; page last updated 2026-02-12. The page does not itself describe the Article 36 and 37 rewards, which come from E4.

    Evidence that argues against this (1)
    • A statute or a programme page states what the law PERMITS, not how the agency exercises the discretion the law gives it. Every operative term here — serious condition, substantial improvement, unmet need, plausible medical use — is applied case by case and the reasoning is not published, so the text bounds the outer edge of what could happen and predicts nothing about a particular application. The exemptions are the operative part: deferral and waiver are granted routinely, and a PIP agreed at marketing authorisation can have completion dates years later, so the requirement's existence does not imply paediatric data at approval. European Medicines Agency 2026
  3. E3strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.database

    EMA's class waiver list, updated 2 June 2025 and superseding previous class waiver decisions, exempts named classes of medicines from the PIP requirement including those intended for conditions that occur only in adult populations, and covers malignant neoplasms of the breast, prostate, lung, intestinal and gynaecological sites; it does not list acute leukaemia.

    Class waivers · European Medicines Agency, Paediatric Committee · EMA 2025
    What this evidence cannot show

    Retrieved 2026-09-18 via automated page summarisation. The summariser reported that 'leukaemia' does not appear in the list but did report 'mature B, T and NK cell neoplasms' and 'myeloproliferative neoplasms'; the full decision annex should be read verbatim before relying on the exclusion of any specific haematological entity.

    Evidence that argues against this (1)
    • In at least one therapeutic area the waiver is not an escape route but the normal outcome. A systematic scrutiny of the EMA PIP repository identified 1,866 PIPs overall, of which 12% concerned cardiovascular medicines -- the largest single therapeutic area by PIP count -- and found that 71.9% of the cardiovascular PIP decisions were FULL WAIVERS, so the product would not be studied in children at all; only 14% of established paediatric cardiovascular needs were addressed by a positively decided PIP. This does not establish the waiver rate for haematological oncology, which is the gap this entry should close, but it shows that 'not class-waived' is a long way from 'will be studied'. Abstract read via PubMed; the paper is open access (Pharmaceutics 12(12):1176) and the full text was not read. Faulkner B et al. 2020
  4. E4established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.database

    Article 36(1) of Regulation (EC) No 1901/2006 entitles the holder of a patent or SPC to a six-month SPC extension where an application includes the results of all studies conducted in compliance with an agreed paediatric investigation plan; Article 37 extends the ten-year orphan market exclusivity under Article 8(1) of Regulation (EC) No 141/2000 to twelve years in the same circumstances for a designated orphan medicinal product.

    Regulation (EC) No 1901/2006, Articles 36 and 37 · European Parliament and Council of the European Union · Official Journal of the European Union, L 378/1 2006
    What this evidence cannot show

    Article 36(1) also requires, in its full text, that the information on the studies appear in the product information and, in the relevant version, that the product be authorised in all Member States; those conditions were not read verbatim here.

    Evidence that argues against this (1)
    • Agreeing a PIP and completing one are very different events, and the infant band is the worst served. A cross-sectional analysis of the 121 active pharmaceutical ingredients on the EMA/Paediatric Working Party priority list for off-patent medicines found that 33 had an agreed PIP and only SIX of those 33 were completed. In the same sample, SmPC guidance for paediatric use was present for adolescents in 70% and children in 70% of ingredients but for infants in only 49% and neonates in only 41%. The Article 36/37 rewards this evidence item describes are contingent on completing an agreed plan, and completion in this sample ran at roughly one in five. Abstract read via PubMed; full text not read. Mogensen AKB et al. 2022
  5. E5established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.database

    The European Commission granted orphan designation EU/3/21/2569 for the treatment of acute myeloid leukaemia to Syndax Europe B.V. on 14 January 2022, for the active substance corresponding to revumenib, described as disrupting the interaction between KMT2A and menin.

    EU/3/21/2569 - orphan designation for treatment of acute myeloid leukaemia · European Medicines Agency · EMA orphan designation register 2022
    What this evidence cannot show

    The EMA record names the substance by full chemical name rather than by INN; identification as revumenib rests on sponsor (Syndax Europe B.V.), the menin-KMT2A mechanism description and the date.

    Evidence that argues against this (1)
    • An orphan designation is granted on prevalence and plausible benefit at the time of application, is separate from marketing authorisation, and can be withdrawn or lapse without the product ever being approved in the EU. It records an intention, not a status. European Medicines Agency 2026
  6. E6weak confidence 2 of 5: Preliminary, small, indirect, or not yet peer reviewed.database

    As of 2026-09-18 no EU marketing authorisation, EPAR or published paediatric investigation plan decision could be located for revumenib or ziftomenib; the expected EPAR URL for Revuforj returns HTTP 404 and EMA's public search endpoints returned HTTP 401 security-verification responses to automated queries.

    What this evidence cannot show

    This is an absence-of-retrieval finding, deliberately marked weak. EMA's search and PIP-listing pages blocked automated access, and EMA records the active substance by chemical name rather than INN, so a PIP decision or an ongoing evaluation could exist without surfacing in these searches. It should be re-checked manually against EMA's PIP register and the CHMP agendas before being treated as settled.

    Evidence that argues against this (1)
    • An absence observed through a public search interface on one date bounds what that interface returns, not what exists. Regulatory documents are published on lags that differ by agency and by document type, a 404 can reflect a URL scheme change, and designations under several of these programmes are explicitly not publicly disclosable — so the absence is partly structural. European Medicines Agency 2026
  7. E7strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.review

    A review of 147 oncology class waivers granted under the European Paediatric Regulation between June 2012 and June 2015, covering 89 drugs, found that 48 (54%) had a mechanism of action warranting paediatric development, and the authors called for suppression of Article 11(1)(b), the ground permitting waivers because the associated condition does not occur in children.

    From class waivers to precision medicine in paediatric oncology · Pearson ADJ, Pfister SM, Baruchel A, Bourquin JP, Casanova M, Chesler L, Doz F, Eggert A, Geoerger B, Jones DTW, Kearns PR, Molenaar JJ, Morland B, Schleiermacher G, Schulte JH, Vormoor J, Marshall LV, Zwaan CM, Vassal G · The Lancet Oncology 18(7):e394-e404 2017
    PMID 28677575DOI
    What this evidence cannot show

    Covers 2012-2015 and predates both the 2015 class waiver overhaul and the 2 June 2025 revision, so the specific counts are historical. The mechanism-of-action argument it makes is the one that drove subsequent reform. Retrieved via PubMed.

    Evidence that argues against this (1)
    • A caution in the other direction on this entry's central claim. The EMA's own Paediatric Committee and Committee for Orphan Medicinal Products members published a comparative analysis of PIP conditions against orphan designation conditions and reported that 'in the substantial majority of cases there is no divergence between the conclusions of COMP and PDCO with regard to the condition for which a medicine is to be developed', concluding that the two Regulations work synergistically for rare childhood disease. This is a regulator-authored paper and should be weighted accordingly, but it is the published rebuttal to the 'PIP scoping is used to exclude children' reading, and this entry currently records only the critical side. Abstract read via PubMed; full text not read. Ecker A et al. 2017
  8. E8established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.database

    Revumenib was approved in the United States on 2024-11-15 for relapsed or refractory acute leukaemia with a KMT2A translocation in adult and paediatric patients 1 year and older, with FDA waiving the paediatric study requirement for patients under 1 year of age as impossible or highly impracticable.

    NDA 218944 Approval Letter, REVUFORJ (revumenib) tablets · US Food and Drug Administration, Center for Drug Evaluation and Research · Drugs@FDA (218944Orig1s000ltr.pdf) 2024
    What this evidence cannot show

    Included here for the transatlantic comparison; it is a US document and says nothing about EU obligations. See reg-breakthrough-and-accelerated-approval for the full quotation.

    Evidence that argues against this (1)
    • The US waiver of the paediatric study requirement is the load-bearing part of this item and it has a specific meaning: FDA waives where studies are impossible or impracticable, or where the drug is ineffective or unsafe in that group. Which ground was used determines whether the waiver is a statement about feasibility or about the drug, and the approval letter's language should be quoted rather than summarised. U.S. Food and Drug Administration 2026
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