1

A Bayesian Non-Inferiority Appr

oach to
Evaluation of Bridging Studies
Chin-Fu Hsiao, Jen-Pei Liu
Division of Biostatistics and Bioinformatics
National Health Research Institites

Huey-Miin Hsueh
Department 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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Introduction
ICH (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 rea
dily interpreted as capable of “bridging” the foreign data
• If a bridging study, properly executed, indicates that a diff
erent dose in the new region results in a safety and efficacy
profile that is not substantially different from that derive
d in the original region, it will often be possible to extrapol
ate the foreign data to the new region, with appropriate dos
e adjustment, if this can be adequately justified (e.g., by ph
armacokinetic 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 Approach

Step 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 placebo
Step 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 regions
Step 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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Region Statistics Treatment Group

Drug Placebo
Original 1 N 138 132
Mean -18 -3
Standard Deviation 11 12
Original 2 N 185 179
Mean -17 -2
Standard Deviation 10 11
Original 3 N 141 143
Mean -15 -5
Standard Deviation 13 14
New 1 N 64 65
Mean -4.7 -3.8
Standard Deviation 11 11
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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