Model-Based Assessment of Alternative Study Designs in Pediatric Trials. Part I: Frequentist Approaches.
Alternative designs can increase the feasibility of pediatric trials when compared to classical parallel designs (PaD). In this work we present a model-based approach based on clinical trial simulations for the comparison of PaD with the alternative sequential, crossover, and randomized withdrawal (RWD) designs. Study designs were evaluated in terms of: type I and II errors, sample size per arm (SS), trial duration (TD), treatment exposures, and parameter estimate precision (EP). The crossover requires the lowest SS and TD, although it implies higher placebo and no treatment exposures. RWD maximizes exposure to active treatment while minimizing that to placebo, but requires the largest SS. SS of sequential designs can sometimes be smaller than the crossover one, although with poorer EP. This pharmacometric framework allows a multiscale comparison of alternative study designs that can be used for design selection in future pediatric trials.
Consorzio per Valutazioni Biologiche e Farmacologiche, Pavia, Italy.|Dipartimento di Ingegneria Industriale e dell'Informazione, Università degli Studi di Pavia, Pavia, Italy.
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Smania
Direzione Scientifica Centrale, Fondazione Salvatore Maugeri, IRCCS, Pavia, Italy.
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Baiardi
Consorzio per Valutazioni Biologiche e Farmacologiche, Pavia, Italy.
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Ceci
Dipartimento di Ingegneria Industriale e dell'Informazione, Università degli Studi di Pavia, Pavia, Italy.
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Magni
Consorzio per Valutazioni Biologiche e Farmacologiche, Pavia, Italy.|Department of Clinical Pharmacology, Global Clinical Development, Chiesi Farmaceutici, Parma, Italy.
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D002648:Child; D002986:Clinical Trials as Topic / Q000379:methods*; D018592:Cross-Over Studies; D006801:Humans; D008962:Models, Theoretical; D010372:Pediatrics; D016032:Randomized Controlled Trials as Topic / Q000379:methods; D012107:Research Design; D018401:Sample Size