title: Sample size calculation for recurrent events data in one-arm studies.
abstract: In some exceptional circumstances, as in very rare diseases, nonrandomized one-arm trials are the sole source of evidence to demonstrate efficacy and safety of a new treatment. The design of such studies needs a sound methodological approach in order to provide reliable information, and the determination of the appropriate sample size still represents a critical step of this planning process. As, to our knowledge, no method exists for sample size calculation in one-arm trials with a recurrent event endpoint, we propose here a closed sample size formula. It is derived assuming a mixed Poisson process, and it is based on the asymptotic distribution of the one-sample robust nonparametric test recently developed for the analysis of recurrent events data. The validity of this formula in managing a situation with heterogeneity of event rates, both in time and between patients, and time-varying treatment effect was demonstrated with exhaustive simulation studies. Moreover, although the method requires the specification of a process for events generation, it seems to be robust under erroneous definition of this process, provided that the number of events at the end of the study is similar to the one assumed in the planning phase. The motivating clinical context is represented by a nonrandomized one-arm study on gene therapy in a very rare immunodeficiency in children (ADA-SCID), where a major endpoint is the recurrence of severe infections.
authors.affiliation: Center of Biostatistics for Clinical Epidemiology, Department of Clinical Medicine and Prevention, University of Milano-Bicocca, Monza, Italy. paola.rebora@unimib.it
authors.forename: Paola
authors.initials: P
authors.lastname: Rebora
authors.forename: Stefania
authors.initials: S
authors.lastname: Galimberti
mesh_terms: D000243:Adenosine Deaminase / Q000172:deficiency; D000361:Agammaglobulinemia / Q000628:therapy; D002648:Child; D002986:Clinical Trials as Topic / Q000379:methods*; D003627:Data Interpretation, Statistical; D023381:Endpoint Determination; D015316:Genetic Therapy / Q000009:adverse effects / Q000379:methods; D006801:Humans; D016012:Poisson Distribution; D012008:Recurrence; D015203:Reproducibility of Results; D012107:Research Design; D018401:Sample Size; D016511:Severe Combined Immunodeficiency / Q000628:therapy; D018709:Statistics, Nonparametric; D013997:Time Factors
chemical_list: D000243:Adenosine Deaminase