Sequential design approaches for bioequivalence studies with crossover designs

Potvin, Diane; DiLiberti, Charles E.; Hauck, Walter W.; Parr, Alan; Schuirmann, Donald J.; Smith, Robert A.

doi:10.1002/pst.294

Cited by 87 publications

(205 citation statements)

References 22 publications

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“…Their performance was also quite similar in the absence of futility criteria (1). Differences between methods B and C are most visible when we look at high initial sample size and low variability.…”

Section: Resultsmentioning

confidence: 78%

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Futility Rules in Bioequivalence Trials with Sequential Designs

Fuglsang¹

2013

AAPS J

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Abstract. Health Canada, the US Food and Drug Administration, as well as the European Medicines Agency consider sequential designs acceptable for bioequivalence studies as long as the type I error is controlled at 5%. The EU guideline explicitly asks for specification of stopping rules, so the goal of this work is to investigate how stopping rules may affect type I errors and power for recently published sequential bioequivalence trial designs. Using extensive trial simulations, five different futility rules were evaluated for their effect on type I error rates and power in two-stage scenarios. Under some circumstances, notably low sample size in stage 1 and/or high variability power may be very severely affected by the stopping rules, whereas type I error rates appear less affected. Because applicants may initiate sequential studies when the variability is not known in advance, achieving sufficient power and thereby complying with certain guideline requirements may be challenging and application of optimistic futility rules could possibly be unethical. This is the first work to investigate how futility rules affect type I errors and power in sequential bioequivalence trials.

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Section: Resultsmentioning

confidence: 78%

“…When reading these tables, it can be mentioned that at one 1,000,000 simulations, the type I error rate can be considered statistically significantly inflated at or above 0.0513, while Potvin et al used 0.052 to signify a clinically relevant inflation (1).…”

Section: Resultsmentioning

confidence: 99%

Futility Rules in Bioequivalence Trials with Sequential Designs

Fuglsang¹

2013

AAPS J

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“…When using such a "two-stage" or "add-on" design, appropriate steps must be taken to correct for multiplicity and, therefore, guarantee an overall type I error of 5%, i.e. α = 0.05 (19)(20)(21). The 2010 EMA Guideline on the Investigation of Bioequivalence also allows such a "two-stage" design.…”

Section: Study Conductmentioning

confidence: 99%

“…The 2010 EMA Guideline on the Investigation of Bioequivalence also allows such a "two-stage" design. One possible approach mentioned in this revised EMA bioequivalence guideline is calculating the 94.12% confidence interval, instead of the usual 90% confidence interval, corresponding to an adjusted α of 0.0294, for both the analysis of the stage 1 results as well as the combined results from stage 1 and stage 2 (20).…”

Section: Study Conductmentioning

confidence: 99%

The revised EMA guideline for the investigation of bioequivalence for immediate release oral formulations with systemic action

Verbeeck

Musuamba

2012

J Pharm Pharm Sci

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“…As bioequivalence studies are commonly conducted using crossover study designs, variance estimates are based on a withinparticipant coefficient of variation (CV), and effect size is determined using GMRs of selected parameters for the two formulations. Although a minimum sample size is obtained at perfect equivalence (assumed GMR=1.00), some departure from perfect equivalence is commonly assumed while estimating sample size (Fenta 2014, Potvin et al 2008.…”

Section: Introductionmentioning

confidence: 99%

Relative bioavailability of diazoxide, manufactured at two different international locations, in healthy participants under fasting conditions: an open-label, two-stage, adaptive, sequential two-period crossover study

Behm

Panebianco

et al. 2017

AAPS Open

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Theoretically, calculating the sample size required for achieving the desired power is straightforward with true coefficient of variance (CV) estimates and true test/reference geometric mean ratios (GMRs) of selected parameters. However, true variance estimates are often not known and are, instead, based on published literature or pilot trials. An open-label, two-stage, adaptive, sequential two-period crossover study was used to determine relative bioavailability of a single 100 mg dose of diazoxide manufactured at two different international sites. This design was utilized due to the lack of intra-subject variance estimation data for diazoxide pharmacokinetic parameters. Second-stage sample size was estimated using intra-participant variance from the first stage. Thirty-six healthy adults (age, 18-55 years) were randomized (1:1) to receive a single dose of test/reference product, a single dose of diazoxide (100 mg capsule), under fasting conditions with crossover after 14 days. GMRs (90% confidence interval [CI]) of area under curve from time zero to infinity (AUC 0-inf ) and maximum plasma concentrations (C max ) of test versus reference product were 1.06 (1.03-1.10) and 1.17 (1.14-1.20), respectively. Bioequivalence was declared at stage 1 because 90% CIs were between 0.80 and 1.25; stage 2 was not initiated since the estimated power was >99% for both AUC 0-inf and C max . Results of this study demonstrate efficient use of an adaptive, two-stage sequential design to assess bioequivalence. Similar study design may be effectively used in other bioequivalence studies wherein CV and GMRs of relevant parameters are unknown and sample size estimation is difficult.

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Sequential design approaches for bioequivalence studies with crossover designs

Cited by 87 publications

References 22 publications

Futility Rules in Bioequivalence Trials with Sequential Designs

Futility Rules in Bioequivalence Trials with Sequential Designs

The revised EMA guideline for the investigation of bioequivalence for immediate release oral formulations with systemic action

Relative bioavailability of diazoxide, manufactured at two different international locations, in healthy participants under fasting conditions: an open-label, two-stage, adaptive, sequential two-period crossover study

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