The use of mid-trial reviews for design modifications in small scale clinical studies M.R. Sooriyarachchi a, ⁎, R.V. Jayatillake a , H. Ranganath b , Michael Eddleston c,d a Department of Statistics, University of Colombo, Sri Lanka b South Asian Clinical Toxicology Research Collaboration, Sri Lanka c Clinical Pharmacological Unit, University of Edinburgh, UK d National Poisons Information Service - Edinburgh, Royal Infirmary Edinburgh, Edinburgh, UK article info abstract Article history: Received 12 May 2010 Accepted 22 July 2010 Available online xxxx Many clinical studies such as those in the areas of toxicology, early phase clinical trials and bioequivalence studies use small samples due to the high cost of experimentation. These studies test hypotheses based on small samples. These small samples result in low power and therefore even if the alternative hypotheses may be true the chance of it being rejected is low. The sample size is determined in an ad-hoc way and no proper scientific approach is used. Sample size calculations for clinical studies are usually conducted to determine the total number of patients needed to satisfy a specified power requirement, and their validity is dependent on pre-trial knowledge of nuisance parameters and distributional and modelling assumptions. Another short coming is that often hypotheses are tested without checking the assumptions required by the test. This paper looks at design reviews in the context of small samples. It examines several design modifications done with asmall internal pilot study. In the past similar techniques have been applied to large scale studies but it sperformance is yet to be established in small scale clinical studies thus the contribution of this paper is in justifying the validity of these techniques for small samples too. The methodology is illustrated on an uncontrolled observational toxicology study. In this paper simulations will be presented showing that the design modifications would not influence the type-I error rate and that these would be successful in preserving the power, and the implementation of the design review procedure will be described. © 2010 Elsevier Inc. All rights reserved. Keywords: Internal pilot study Mid-trial design review Normal error linear model Sample size reestimation Testing distributional and modelling assumptions 1. Introduction Wittes and Britain [1], Gould [2,3] and Gould and Shih [4] developed the idea of mid-trial reviews using internal pilot studies for the purpose of estimating unknown parameters required to determine sample size. More recently Zucker et al. [5], Shih [6], Gould [7], Whitehead et al. [8] and Bolland et al. [9] among others discuss the applicability of these mid-trial reviews for making other decisions in addition to estimating unknown parameters. Coffey and Muller [10] use an internal pilot study for fitting a Normal error linear model and estimating the variance required to determine the sample size using the mean square error (MSE) of the model. Friede and Kieser [11] review past studies on this topic. While all these authors have considered the performance of design reviews in large scale clinical trials its validity in small scale clinical studies is yet to be established [12]. The objective of this paper is to examine the performance of several design modifications at the design review, based on a small scale clinical study in order to determine the validity of these methods in small studies. The methods are illustrated on an uncontrolled observa- tional study of the drug atropine in the treatment of Contemporary Clinical Trials xxx (2010) xxx–xxx ⁎ Corresponding author. Department of Statistics, University of Colombo, P.O. Box 1490, Colombo 3, Sri Lanka. Tel.: +94 2590111, +94 5731269; fax: +94 2587239. E-mail address: roshini@mail.cmb.ac.lk (M.R. Sooriyarachchi). CONCLI-00478; No of Pages 8 1551-7144/$ – see front matter © 2010 Elsevier Inc. All rights reserved. doi:10.1016/j.cct.2010.07.011 Contents lists available at ScienceDirect Contemporary Clinical Trials journal homepage: www.elsevier.com/locate/conclintrial Please cite this article as: Sooriyarachchi MR, et al, The use of mid-trial reviews for design modifications in small scale clinical studies, Contemp Clin Trials (2010), doi:10.1016/j.cct.2010.07.011