This lecture will present a general overview, with pros and cons, of the different study design that could be employed for drug evaluation in pediatric rheumatic diseases.
Among the multitude of study designs that could be considered in pediatric rheumatology, the major trial designs are the classic parallel randomized clinical trial (RCT) with placebo or active comparator and the randomized withdrawal design. While the parallel design still remain the gold standard for establishing the efficacy and short-term safety of an experimental agent, disadvantages include ethical concerns due to the use of placebo in children with chronic condition for which alternative treatments are available. The option of using an active control is not feasible due to the high sample size that are required by these kind of trial. The double-blind, controlled, randomized withdrawal design was proposed for the first time by Dr Lovell and Dr Giannini for use in pediatric rheumatology studies in particular for juvenile idiopathic arthritis. Eligible children are treated in an open label fashion with the experimental therapy to be tested in the trial for a few months after which responders (typically defined as those demonstrating an ACR Pediatric 30 response) are randomized in a double-blind fashion either to continue the experimental therapy or to switch to placebo. In this segment of the study, called the double-blind withdrawal phase, patients who demonstrate a pre-defined definition of disease worsening (e.g. “flare”) are withdrawn from the double-blind withdrawal phase and usually re-treated with the experimental therapy in an open label fashion. The withdrawal design has proven to be very effective design and has been used in nearly all recent trials of biologic agents in children with JIA. Data gathered by use of this design led to the approval of biologic agents for children with JIA by both the FDA and EMA.
Disclosure of Interest N. Ruperto Grant/research support from: The Gaslini Hospital, which is the public Hospital where I work as full time public employee, has received contributions from the following industries: Abbott, BMS, “Francesco Angelini”, GlaxoSmithKline (GSK), Hoffman-La Roche, Italfarmaco, Janssen, Novartis, Pfizer, Sanofi Aventis, Schwarz Biosciences, Sobi, Xoma, Wyeth. This money has been reinvested for the research activities of the hospital in a fully independent manners besides any committment with third parties., Speakers bureau: The undersigned Dr Nicolino Ruperto received honoraria for consultancy or speaker's bureau from the following pharmaceutical companies: Abbott, AbbVie, Amgen, Biogenidec, Astellas, Alter, AstraZeneca, Boehringer, BMS, CD-Pharma,Celgene, CrescendoBio, EMD Serono,Hoffman-La Roche, Italfarmaco, Janssen, MedImmune, Medac, Novartis, Novo Nordisk, Pfizer, Sanofi Aventis, Servier, Takeda, Vertex.