Optimal adaptive sequential designs for crossover bioequivalence studies.

In prior works, this group demonstrated the feasibility of valid adaptive sequential designs for crossover bioequivalence studies. In this paper, we extend the prior work to optimize adaptive sequential designs over a range of geometric mean test/reference ratios (GMRs) of 70-143% within each of two ranges of intra-subject coefficient of variation (10-30% and 30-55%). These designs also introduce a futility decision for stopping the study after the first stage if there is sufficiently low likelihood of meeting bioequivalence criteria if the second stage were completed, as well as an upper limit on total study size. The optimized designs exhibited substantially improved performance characteristics over our previous adaptive sequential designs. Even though the optimized designs avoided undue inflation of type I error and maintained power at ≥ 80%, their average sample sizes were similar to or less than those of conventional single stage designs.

Additional results for 'Sequential design approaches for bioequivalence studies with crossover designs'.

In 2008, this group published a paper on approaches for two-stage crossover bioequivalence (BE) studies that allowed for the reestimation of the second-stage sample size based on the variance estimated from the first-stage results. The sequential methods considered used an assumed GMR of 0.95 as part of the method for determining power and sample size. This note adds results for an assumed GMR = 0.90. Two of the methods recommended for GMR = 0.95 in the earlier paper have some unacceptable increases in Type I error rate when the GMR is changed to 0.90. If a sponsor wants to assume 0.90 for the GMR, Method D is recommended. Copyright © 2011 John Wiley & Sons, Ltd.

The use of the InteliSite companion device to deliver mucoadhesive polymers to the dog colon.

The aims of this study were two-fold; first to report on the use of the novel InteliSite Companion device to deliver material to the colon, and second to use this new technology to assess the potential of mucoadhesive polymers to be retained in the large intestine. In this three-way crossover study in beagle dogs, two mucoadhesive polymers and a non-mucoadhesive polymer were remotely delivered in powder form to the colon. The retention of 150mg doses of the radiolabelled mucoadhesive polymers Carbopol 980 and polycarbophil AA-1, and the retention of ethylcellulose (control) in the colon of three canines was examined using gamma scintigraphy. The InteliSite Companion device had a mean gastric emptying time of 1.0+/-0.8h and a mean caecal arrival time of 2.3+/-1.0h. The device was remotely activated to expel the polymers at the caecum. Although incomplete release was noted with all polymers, Carbopol 980 was found to have increased retention in the proximal colon of all three dogs. The mean retention time within the proximal colon for Carbopol 980 (15.3+/-1.4h) was significantly higher than that of polycarbophil AA-1 (10.0+/-5.7h) and the control (7.1+/-1.4h) (p<0.05). The increased colon retention time demonstrated by Carbopol 980 may be suggestive of a mucoadhesive effect.

Sequential design approaches for bioequivalence studies with crossover designs.

The planning of bioequivalence (BE) studies, as for any clinical trial, requires a priori specification of an effect size for the determination of power and an assumption about the variance. The specified effect size may be overly optimistic, leading to an underpowered study. The assumed variance can be either too small or too large, leading, respectively, to studies that are underpowered or overly large. There has been much work in the clinical trials field on various types of sequential designs that include sample size reestimation after the trial is started, but these have seen only little use in BE studies. The purpose of this work was to validate at least one such method for crossover design BE studies. Specifically, we considered sample size reestimation for a two-stage trial based on the variance estimated from the first stage. We identified two methods based on Pocock's method for group sequential trials that met our requirement for at most negligible increase in type I error rate.