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Extrapolation or controlled trials in paediatrics: the current dilemma
  1. Nicolino Ruperto1,
  2. Hermine I Brunner2,
  3. Daniel J Lovell2,
  4. Alberto Martini3
  5. for the Paediatric Rheumatology International Trials Organisation (PRINTO) and the Pediatric Rheumatology Collaborative Study Group (PRCSG)
  1. 1 Pediatria II, Reumatologia–PRINTO, IRCCS Giannina Gaslini, Genova, Italy
  2. 2 Division of Rheumatology–PRCSG, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, USA
  3. 3 Direzione Scientifica, IRCCS Giannina Gaslini, Genova, Italy
  1. Correspondence to Nicolino Ruperto, IRCCS Istituto Giannina Gaslini, Pediatria II–Reumatologia, Pædiatric Rheumatology International Trials Organisation (PRINTO), EULAR Centre of Excellence in Rheumatology 2008-2018, Via Gaslini, 5, 16147 Genova, Italy; nicolaruperto{at}gaslini.org

https://doi.org/10.1136/archdischild-2017-312994

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    Historically, it has been difficult to conduct controlled studies in children because of the paucity of large collaborative research networks, scarce availability of funding and lack of interest from pharmaceutical companies. Thanks to the Best Pharmaceuticals for Children Act in USA and to a dedicated legislation for paediatric medicines development (Paediatric Regulation) in the European Union, this dire situation is very much improved.1 2

    Undoubtedly, in some paediatric specialities, such as paediatric rheumatology, this legislation has been a great success.3 At least to some extent, this success seems attributable to the existence of two large networks, namely the Pediatric Rheumatology Collaborative Study Group (PRCSG) (www.prcsg.org), covering North America, and the Paediatric Rheumatology International Trials Organisation (PRINTO) (www.printo.it), covering more than 60 countries worldwide.4 Through coordinated and collaborative activities over the preceding two decades, these two networks have effectively worked in academia (over 35 000 children enrolled in not-for-profit studies) and with various pharmaceutical companies and succeeded to help enrol more than 3000 children at over 250 centres from 39 countries in international clinical trials.5–12 Indeed, all studies of biological medications by these two networks, with the exception of the infliximab trial (see later),6 have led to a marketing authorisation for juvenile idiopathic arthritis (JIA).

    Stefanska and colleagues from the European Medicine Agency (EMA) report their personal views of the EMA’s framework document addressing data extrapolation to facilitate future programmes in the paediatric field.13 The review is centred on examples in the paediatric immune-mediated inflammatory disorders, namely on JIA, juvenile psoriasis and inflammatory bowel disease.

    Controlled trials versus extrapolation

    Undoubtedly, the double-blind, placebo-controlled study design still provides the most stringent scientific evidence in support of the benefits and safety of drug candidates. However, there are several considerations specific to paediatrics that make the use of double-blinded, placebo-controlled studies less …

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    Footnotes

    • Contributors NR drafted the first version, which was subsequently revised by HIB, DJL and AM.

    • Competing interests NR has received grants from BMS, Hoffman-La Roche, Janssen, Novartis, Pfizer, Sobi during the conduct of the study, and personal fees and speaker honorarium from AbbVie, Ablynx, Amgen, AstraZeneca, Baxalta Biosimilars, Biogen Idec, Boehringer, Bristol Myers Squibb, Celgene, Eli-Lilly, EMD Serono, Gilead Sciences, Janssen, Medimmune, Novartis, Pfizer, R-Pharm, Roche, Sanofi, Servier and Takeda. HIB reports grants/research support from National Institutes of Health, NIAMS; HIB has also received consultancy fees from AstraZeneca, Bristol-Myers Squibb, AbbVie, Pfizer, Roche, Novartis, UBC, Forest Research Institute, Horizon, Johnson & Johnson, Biogen, Takeda, Genentech, GlaxoSmithKline, Boehringer Ingelheim, Celgene, Janssen; speaker bureaus from Genentech. DJL reports grants/research support from National Institutes of Health, NIAMS; DJL has also received consultancy fees from AstraZeneca, Bristol-Myers Squibb, AbbVie, Pfizer, Roche, Novartis, UBC, Forest Research Institute, Horizon, Johnson & Johnson, Biogen, Takeda, Genentech, GlaxoSmithKline, Boehringer Ingelheim, Celgene, Janssen, and speaker bureaus from Genentech. Starting 1 March 2016 AM became the Scientific Director of the G Gaslini Hospital; therefore his role does not allow to render private consultancies resulting in personal income. AM has performed consultancy activities on behalf of the Gaslini Institute for the following companies: AbbVie, Boehringer, Novartis and R-Pharm. The money received for these activities are directly transferred to the Gaslini Institute’s bank account.

    • Provenance and peer review Commissioned; internally peer reviewed.

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