TABLE 2.

Scenarios for cancer drug development since the implementation of the Paediatric Medicine Regulation in the EU

#	Adults	Children	Examples	Compliance with PMR
1	Drug developed and marketed	Subsequently developed for the paediatric. population, BUT: same indication as adults	Delayed development of BCR/ABL‐inhibitors for Ph + chronic myeloid leukaemia ➔ MA for dasatinib in adults in 2006 (USA and EU), for children in 2017 (USA) and 2018 (EU) Waiver for crizotinib on the grounds that lung cancer does not occur in children	Not in compliance. If the disease occurs both in adults and children, paediatric development should not be delayed (nor waivered)
2	Drug developed and marketed	Developed in parallel in children with a different indication ➔ based on mechanism of action, not on disease indication	Parallel development of BRAF inhibitors for melanoma and lung cancer in adults, AND for BRAF‐mutated brain tumours and histiocytosis in children Agreed PIP for the combination of dabrafenib + trametinib for glioma with BRAF‐V600 mutations (1–18‐year‐old patients)	In compliance. PIP should be submitted not later than after completing PK studies in adults, if PMR is implemented BUT: the possibility of deferral on the initiation of the PIP studies results often in delays
3	Drug developed but NOT marketed	Development stopped even though scientific rationale for developing drug in paediatric population	Development of IGF1‐R antibodies was stopped due to failure for adult indications (lung, breast, pancreatic cancer) ➔ despite compelling pre‐clinical and early‐phase clinical evidence of potential benefit in children, especially in Ewing sarcoma	This is in compliance with PMR and a result of lack of (economic) incentives for companies to continue paediatric development if there is no market benefit in adults
4	No	Drug developed and marketed first‐in‐paediatric. population ➔First‐in‐child MA	Dinutuximab (MA in 2015 in EU and USA), first‐in‐class anti‐GD2 antibody for neuroblastoma	Not driven by the PMR. The initial effort was done by academia, followed by industry‐led development, motivated by US incentives The company benefited from the US Creating Hope Act ➔ Transferable Priority Review Voucher

Abbreviations: IGF1‐R, anti‐Insulin‐like growth factor 1 Receptor; MA, Marketing authorization; NA, Not Applicable; PD‐1, Programmed cell death protein; PIP, Paediatric Investigation Plan; PK, pharmacokinetic; PMR, Paediatric Medicine Regulation.