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A Bayesian Non-Inferiority Appr

oach to

Evaluation of Bridging StudiesChin-Fu Hsiao, Jen-Pei Liu

Division of Biostatistics and Bioinformatics

National Health Research Institites

Huey-Miin HsuehDepartment of Statistics

National Cheng-Chi University

The views expressed in this paper are professional opinions of the

presenter and may not necessarily represent the position of the

National Health Research Institutes, Taiwan

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Outline

• Introduction

• Bridging Study

• A Bayesian Non-Inferiority Approach

• Discussion

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IntroductionICH (International Conference on Harmonisa

tion) E5

Ethnic Factors in the Acceptability of

Foreign Clinical Data

The purpose of this guidance is to facilitate the

registration of medicines among ICH regions

by recommending a framework for evaluating

the impact of ethnic factors upon a medicine’s

effect, i.e., its efficacy and safety at a particular

dosage and dose regimen.

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Objectives of ICH E5

• To describe the characteristics of foreign clinical data that will facilitate their extrapolation to different population

and support their acceptance as a basis for registration on a medicine in a new region

• To describe regulatory strategies that minimize duplication of clinical data and facilitate acceptance of foreign clinical data in the new region

• To describe the use of bridging studies, when necessary, to allow extrapolation of foreign clinical data to a new region

• To describe development strategies capable of characterizing ethnic factor influences on safety, efficacy, dosage, and dose regimen

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Bridging Study

A bridging study is defined as a study

performed in the new region to provide

pharmacodynamic or clinical data on efficacy,

safety, dosage, and dose regimen in the new region

that will allow extrapolation of the foreign clinical

data to the population in the new region

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Extrapolation and Similarity

• If the bridging study shows that dose response, safety and efficacy in the new region are similar, then the study is readily interpreted as capable of “bridging” the foreign data

• If a bridging study, properly executed, indicates that a different dose in the new region results in a safety and efficacy profile that is not substantially different from that derived in the original region, it will often be possible to extrapolate the foreign data to the new region, with appropriate dose adjustment, if this can be adequately justified (e.g., by pharmacokinetic and/or pharmacodynamic data).

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Bridging Studies

• ICH E5

• Only after the medicine is approved in

the original region

• Performed in the new region

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Bayesian Approach For bridging studies• Small sample size

• No power

• Information on dose response, efficacy and safety of the original region can not be concurrently obtained from the local bridging studies but are available in the trials conducted in the original region

• Need to borrow “strength” from CCDP of the original region

• Information on dose response, efficacy and safety of the original region can and should be incorporated in a statistically sound manner to evaluate bridging evidence by local bridging studies.

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Bayesian Non-Inferiority ApproachStep 1: From the complete clinical data package, use the technique of meta-analysis to integrate the results from the original region to formulate the mean and variability of the prior distribution for test product and placeboStep 2: Use the data from the bridging study in the new region and prior distribution to obtain the mean and variability of the posterior distribution for the difference of test products between new and original regionsStep 3: Evaluate the posterior probability that difference is greater or equal to some clinically acceptable limit Step 4: If the posterior probability is sufficiently large, say 80%, then conclude the similarity between the new and original regions.

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Assumption and Notation

• Assess similarity of efficacy for comparing a test product and a placebo control

• Since the test product has been already approved in the original region due to its proven efficacy against placebo control, the concept of non-inferiority is referred to as the similarity between the treatment effects from both regions

P indicates the common placebo effect for both new and original regions

NT(OT) represents the treatment mean for the new (original) region

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Similarity

Given the data from the bridging study and prior

information on (P, NT, OT) formulated from the

CCDP, we claim similarity on efficacy for the new

region in terms of non-inferiority concept if the

posterior probability

PSI = P{NT- OT >-δ | bridging data and prior }

> 1-for some pre-specified δ> 0 and > 0

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The Equivalence Limit

The equivalence limit δ can be expressed as a

proportion of the relative efficacy of the test

product against placebo

δ=f(OT- P)

where f is a fixed pre-specified constant and

0<f<1.

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Example• We hypothesize an example based on our

experience from literature review• We select four randomized studies of the effect of

a test drug (versus placebo) in reducing the sitting diastolic blood pressure

• The results of three studies are treated as the data from the original region, while the other one study is treated as the data from the new region

• The alternative hypothesis of interest is that the difference of reduction from baseline in sitting diastolic blood pressure between the test drug and placebo is less than 0

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Treatment Group Region Statistics

Drug Placebo

Original 1 N

Mean

Standard Deviation

138

-18

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132

-3

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Original 2 N

Mean

Standard Deviation

185

-17

10

179

-2

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Original 3 N

Mean

Standard Deviation

141

-15

13

143

-5

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New 1 N

Mean

Standard Deviation

64

-4.7

11

65

-3.8

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Example• By letting f=0.5, we obtain that PSI=0.9999

• We therefore conclude that the efficacy observed in the bridging study of the new region is similar to the efficacy from the original region by the concept of non-inferiority

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Discussion

• From our example, it can be seen that all the results from the original region are very significant, while the results from the new region are not significant at all

• Even so, the Bayesian non-inferiority approach still conclude the similarity of efficacy between both regions

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Discussion

• One way to resolve issue is to use weights other than sample size to combine the data from both regions

• Another approach is to use different prior. For the data given above and under the non-informative prior, the posterior probability of non-inferiority, PSI is 0.3228