Blinded sample size recalculation in multicentre trials with normally distributed outcome

Abstract

The internal pilot study design enables to estimate nuisance parameters required for sample size calculation on the basis of data accumulated in an ongoing trial. By this, misspecifications made when determining the sample size in the planning phase can be corrected employing updated knowledge. According to regulatory guidelines, blindness of all personnel involved in the trial has to be preserved and the specified type I error rate has to be controlled when the internal pilot study design is applied. Especially in the late phase of drug development, most clinical studies are run in more than one centre. In these multicentre trials, one may have to deal with an unequal distribution of the patient numbers among the centres. Depending on the type of the analysis (weighted or unweighted), unequal centre sample sizes may lead to a substantial loss of power. Like the variance, the magnitude of imbalance is difficult to predict in the planning phase. We propose a blinded sample size recalculation procedure for the internal pilot study design in multicentre trials with normally distributed outcome and two balanced treatment groups that are analysed applying the weighted or the unweighted approach. The method addresses both uncertainty with respect to the variance of the endpoint and the extent of disparity of the centre sample sizes. The actual type I error rate as well as the expected power and sample size of the procedure is investigated in simulation studies. For the weighted analysis as well as for the unweighted analysis, the maximal type I error rate was not or only minimally exceeded. Furthermore, application of the proposed procedure led to an expected power that achieves the specified value in many cases and is throughout very close to it.

Use of functional imaging across clinical phases in CNS drug development

“…Phase I trials ‘test an experimental drug or treatment in a small group of people 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79 for the first time to evaluate its safety, determine a safe dosage range and identify side effects' (www.clinicaltrials.gov). Few drugs (approximately 1 in 10) that are evaluated in preclinical phases make it to phase I testing in humans.…”

“…One of the big issues with clinical trials relates to the nature of the study design and the variability of data acquired, especially in subjective ratings. 53, 54, 55 Clearly diminishing variance allows for a number of benefits including fewer patients required for adequate power of the study and fewer patients are exposed in a drug trial. Both elements have important cost-related benefits.…”

Blinded and unblinded sample size reestimation procedures for stepped‐wedge cluster randomized trials

“…However, while some results exist on SSRE in multicentre (Jensen & Kieser, 2010) and parallel group CRTs (van Schie & Moerbeek, 2014), no work has established methodology for SSRE in SW‐CRTs, with the increased complexity in the design of SW‐CRTs necessitating a specialised approach. In this article, we address this by developing and exploring the performance of both blinded and unblinded SSRE procedures for cross‐sectional SW‐CRTs.…”

Blinded and unblinded sample size reestimation in crossover trials balanced for period

“…Consequently, Gould and Shih (1992) explored several approaches for reestimating the required sample size in a blinded manner. Jensen & Kieser, 2010;and Togo & Iwasaki, 2011), with these methods also gaining regulatory acceptance (CHMP, 2007;FDA, 2010). More recently, much work has been conducted on similar methods for an array of possible trial designs and types of outcome variable (see, e.g.…”

“…More recently, much work has been conducted on similar methods for an array of possible trial designs and types of outcome variable (see, e.g. Jensen & Kieser, 2010;and Togo & Iwasaki, 2011), with these methods also gaining regulatory acceptance (CHMP, 2007;FDA, 2010).…”