title: A SAS-based solution to evaluate study design efficiency of phase I pediatric oncology trials via discrete event simulation.
abstract: Previous exploration of oncology study design efficiency has focused on Markov processes alone (probability-based events) without consideration for time dependencies. Barriers to study completion include time delays associated with patient accrual, inevaluability (IE), time to dose limiting toxicities (DLT) and administrative and review time. Discrete event simulation (DES) can incorporate probability-based assignment of DLT and IE frequency, correlated with cohort in the case of DLT, with time-based events defined by stochastic relationships. A SAS-based solution to examine study efficiency metrics and evaluate design modifications that would improve study efficiency is presented. Virtual patients are simulated with attributes defined from prior distributions of relevant patient characteristics. Study population datasets are read into SAS macros which select patients and enroll them into a study based on the specific design criteria if the study is open to enrollment. Waiting times, arrival times and time to study events are also sampled from prior distributions; post-processing of study simulations is provided within the decision macros and compared across designs in a separate post-processing algorithm. This solution is examined via comparison of the standard 3+3 decision rule relative to the "rolling 6" design, a newly proposed enrollment strategy for the phase I pediatric oncology setting.
authors.affiliation: Clinical Pharmacology & Therapeutics Division, The Children's Hospital of Philadelphia, USA. barrettj@email.chop.edu
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Barrett
authors.forename: Bhuvana
authors.initials: B
authors.lastname: Jayaraman
authors.forename: Dimple
authors.initials: D
authors.lastname: Patel
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Skolnik
mesh_terms: D002648:Child; D002985:Clinical Protocols; D017321:Clinical Trials, Phase I as Topic / Q000706:statistics & numerical data*; D003627:Data Interpretation, Statistical; D006801:Humans; D015233:Models, Statistical; D009369:Neoplasms / Q000188:drug therapy; D012984:Software; D012985:Software Design