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Multi-Regional Studies and Bridging Studies
Simon Day, PhD
Johns Hopkins University
Rationale
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New/different region
New age group
Changes in vaccine manufacture, storage, etc.
Others?
3
ICH E5
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Adopted 1998
Evaluate the impact of ethnic factors on efficacy and safety
Minimize duplication of clinical data
Context of extrapolation
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ICH E5
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The key terms
− Bridging
− Extrapolation
− Generalization
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ICH E5
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Ethnic differences may affect safety, efficacy, dosage, dose
regimen
Characterize medicines as “ethnically sensitive” or “ethnically
insensitive”
In contrast to “intrinsic” factors and “extrinsic” factors
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Ethnic Sensitivity
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Pharmacokinetics
Pharmacodynamics
Therapeutic range
Metabolism
Bioavailability
Potential for interactions
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Genetic polymorphisms
Intersubject variability
Systemic mode of action
Potential for inappropriate use
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Intrinsic and Extrinsic Factors
Classification
Factor
Description
Intrinsic
Genetic
Gender, race
Polymorphisms
Extrinsic
Physiology and
Age
pathology
Liver, kidney, CV
Environmental
Climate, pollution
Cultural
Socioeconomic factors
Educational status
Medical practice
Diagnostic and
treatment approach
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“Bridging Studies”
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To avoid replication of large, expensive trials
To avoid replication of whole development programmes
To fill in the gaps
To show relevance (i.e., link or build a bridge) between completed
studies and local (regional) factors
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When Are Bridging Studies Needed?: An Overview
No bridging
Bridging
Insensitive to
ethnic factors
Sensitive to ethnic
factors
Region
Similar
Dissimilar
Medical practice
Similar
Different: need
controlled trials
Familiar: need only
pharmacodynamics
Unfamiliar: need
controlled trials
Sufficient
Insufficient: need
controlled trials
Study medication
Drug class
Clinical experience
10
Meets Reg.
Requirements
Extrapolation
Appropriate
Further
Studies
Yes
Yes
None
Yes
No
No
Yes
No
No
Acceptable (New) Package
Original Clinical Data Package
When Do You Need What?
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When Do You Need What?
Original Clinical Data Package
Meets Reg.
Requirements
Yes
Yes
No
No
12
Original Clinical Data Package
When Do You Need What?
Meets Reg.
Requirements
Extrapolation
Appropriate
Yes
Yes
Yes
No
No
No
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When Do You Need What?
Extrapolation
Appropriate
Yes
Yes
Yes
No
No
Further
Studies
None
Bridging
Studies
Acceptable (New) Package
Original Clinical Data Package
Meets Reg.
Requirements
No
14
When Do You Need What?
Original Clinical Data Package
Meets Reg.
Requirements
Yes
Yes
No
No
15
When Do You Need What?
Original Clinical Data Package
Meets Reg.
Requirements
Extrapolation
Appropriate
Yes
Yes
No
Yes
No
No
16
When Do You Need What?
Extrapolation
Appropriate
Further
Studies
Yes
Clinical
Studies
Yes
No
Yes
No
No
Acceptable (New) Package
Original Clinical Data Package
Meets Reg.
Requirements
17
When Do You Need What?
Extrapolation
Appropriate
Further
Studies
Yes
Clinical
Studies
Yes
No
Yes
No
No
Acceptable (New) Package
Original Clinical Data Package
Meets Reg.
Requirements
Bridging
Studies
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Meets Reg.
Requirements
Extrapolation
Appropriate
Further
Studies
Yes
Yes
None
Yes
No
No
No
Yes
Acceptable (New) Package
Original Clinical Data Package
When Do You Need What?
Bridging
Clinical
No
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International Nature of Endpoints
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Thresholds for seeking medical attention
Thresholds for treating (or not) the disease
Varying health care systems
− Payment
− Primary/referral
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Cultural Nature of Endpoints
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Example
− “Have you ever thought about committing suicide?”
Example
− Resource utilisation
− Cost effectiveness studies
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Post-Hoc Arguments: For and Against
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Justifications are always easy but usually futile
We do multi-centre (-country; -region) trials because . . .
− It increases recruitment rate
− It (Informally) gives “wider applicability”
“Wider applicability” is lost if opportunity is not taken
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What Population (Indication)
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“. . . to what population will the results apply?”
− Consider before the trial to what population (not sample) you
want the results to apply
− Consider after the trial to what population the results might be
expected to apply
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In the Next Lecture We’ll Look at . . .
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Interim monitoring
− Some history
− Data monitoring committees
− Individual responsibilities
− Other trial “committees”
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