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Evaluation System of Bridging
Study in Taiwan
Chien-Hua Wu
Statistical Reviewer at CDE
Oct. 2, 2002
The views expressed in this presentation are not necessary
those of Center for Drug Evaluation in Taiwan
77 Announcement
• On July 7th 1993, 40 evaluable patients was
required for registration in Taiwan
• Receive the marketing exclusivity for 5
years
1212 Announcement
• Due to world trade barrier for 77 Announcement
• Bridging study was proposed on Dec. 12th, 2000
• Transitional period from 2000 to 2003, sponsor
have choice to conduct either 40-evalauble
patients or bridging study
• Bridging study will be completely required after
Jan. 1, 2004
• But no marketing exclusivity for bridging study
Evaluation Process
Sponsor
• Bridging data package
• Summary of selfevaluation
BPA
Checking
list
Consultants
Supplemental
documents
Bridging Study
not required
Bridging Study
required
CDE
acceptance
Internal review
meeting
sponsor meeting
Drug review
committee
Accessing the Requirement of a
Bridging Study
Does the drug meet DOH announcements for
waiving a bridging study and the requirements
of submitting ethnic insensitivity data?
Yes
No
Submit relevant documents
according to DOH
announcements and request
for waiving bridging studies
Yes
Does the package include
clinical data of Asian
populations*?
Does the submitted preclinical and
clinical data package meet the
regulatory requirements?
No
Submit additional
relevant information
Does the package include clinical data of Asian populations*?
Yes
No
Have any early phase or global
clinical trials that meet the DOH
requirements of bridging studies
been conducted in Taiwan?
Is the medicine sensitive to both
intrinsic and extrinsic factors?
Are the clinical differences in efficacy
and safety significant?
Yes
Yes
Bridging
study
required
Is the result acceptable
as a bridging study?
Yes
No
bridging
study
required**
No
No
Is it reasonable to extrapolate
from foreign clinical data that the
medicine is insensitive to both
intrinsic and extrinsic factors in
Asians and that its clinical
differences in efficacy and safety
are acceptable? (See ICH E5
guidelines)
No
No
bridging
study
required
Is it reasonable to extrapolate from foreign clinical data that the
medicine is insensitive to both intrinsic and extrinsic factors in Asians
and that its clinical differences in efficacy and safety are acceptable?
Yes
No bridging
study required
No
Is it reasonable to extrapolate from foreign clinical data
that the concentration (dose)-response relationship is
similar between foreign and Asian populations ?
No
Yes
No bridging
study required
Are PK and/or PD data of Asian populations available for
dosage adjustment or efficacy/safety predication?
Yes
Available data will be used
directly to estimate the proper
dosage for Chinese populations.
No
Bridging study required
CDE Bridging Study Evaluation
Items (1)
1.
2.
3.
4.
Linearity PK profile
Steep PD profile
Narrow therapeutic dose range
Highly metabolized through a single pathway,
potential drug-drug interaction
5. Genetic polymorphism (e.g. CYP2D6,
CYP2C19, etc.)
6. Administration as a prodrug.
7. High inter-subject variation in biovailability
CDE Bridging Study Evaluation
Items (2)
8. Low bioavailability, susceptible dietary
absorption effect
9. High likelihood of use in a setting of
multiple co-medications
10. High likelihood for inappropriate use
11. Different indications and/or epidemiology
12. Other important factors of ethnic
sensitivity (e.g. medical practice)
Results of BS Evaluation from
Jan. 1, 2001 to July 31, 2002
I
26
 Case evaluated
(40)
II
14
I
18 (69%)
 BS waived
(29)(73%)
II
I: With Asian data;
II: Without Asian data
11 (79%)
Statistical Approaches of
Bridging Study
Chien-Hua Wu
Assistant Professor
National Taipei University
Oct. 2, 2002
Outline
• Weakness of Evaluation System in CDE
• Strategy for Bridging Study
• Statistical Approaches to Detect the Ethnic
Sensitivity
• Dose Adjustment
• Sample Size Reduction
Bridging Study Evaluation in
Taiwan (1)
• “Assessment of the extrapolation of foreign
clinical data for registration purposes”
published by Lin et. al. in Drug Information
Journal (2002)
Bridging Study Evaluation in
Taiwan (2)
Bridging Study Evaluation in
Taiwan (3)
• 7 of 20 cases considered ethnic difference between
original country and Taiwan in 2001
• 5 of 7 cases were related to safety issues
• 2 cases due to lack of sufficient data to support
efficacy in original country
• Conclusion: it seems like using PK/PD profile
may not be able to tell the ethnic sensitivity in
some circumstance
CDE Bridging Study Evaluation
Items (1)
1.
2.
3.
4.
Linearity PK profile
Steep PD profile
Narrow therapeutic dose range
Highly metabolized through a single
pathway, potential drug-drug interaction
5. High inter-subject variation in
biovailability
CDE Bridging Study Evaluation
Items (2)
8. Low bioavailability, susceptible dietary
absorption effect
9. High likelihood of use in a setting of
multiple co-medications
10. High likelihood for inappropriate use
11. Different indications and/or epidemiology
12. Other important factors of ethnic
sensitivity (e.g. medical practice)
Weakness of Evaluation System
in CDE
• If 1st item fails but not for the rest of it, can we
conclude that there is an ethnic difference???
• PK/PD profile may not be able to judge the ethnic
difference if few evaluated items do not fit well
• According ICH E5, the acceptability of foreign
data should be evaluated based on similarity of
dose response, efficacy and safety between foreign
and new region
Strategy for Bridging Study
Step 1: Detect ethnic sensitivity by looking at the
PK/PD evaluation items and using statistical
approaches
Step 2: No need to conduct a bridging trial if there is
no sufficient evidence to tell the ethnic difference
between original region and local region
Step 3: Adjust dose if ethnic difference does exist
Step 4: Conduct a bridging trial to show efficacy in
the local region using new dose
Statistical Approaches to Detect
Ethnic Sensitivity
1. Check treatment by region interaction
2. Reproducibility and generalizability
probability (Shao and Chow (2002))
3. Conduct a non-inferiority or equivalent
trial
4. Conduct a local trial for 40 evaluable
patients (Baysian approach)
5. Conduct a multinational trial
1st Statistical Approach:
Treatment by Region Interaction
• H0: No Interaction
• Fail to reject the interaction does not mean there
are no differences between two regions.
• HA: Treatment effect is different between two
regions
• Magnitude of difference is of any clinical
relevance? Sufficient sample size?
• See Comments from ICSA (2002)
2nd Statistical Approach:
Reproducibility Probability
• “Reproducibility probability in clinical
trials” by Shao J. and Chow S.C. (2002)
Reproducibility Probability
• H0: 1-2=0
• Power of test statistic: function of =(12)/(1/n1+1/n2)(1/2)
• Replace parameter  by its estimate T(x)
• Reproducibility probability: estimated
power
Evaluation Process for Bridging
Study
Step 1: If the reproducibility probability fails
to meet regulatory requirement of
reproducibility, say >80%, then bridging
study is not needed.
Step 2: Measure the signal-to-noise for
population difference
Step 3: Compute the generalizability
probability
Generalizability Probability
• When the study drug product is applied to a
similar but different patient population in the new
region, it is expected that the mean and variance of
response will be different.
• Population mean difference change to 1- 2+
• Population variance change to C2 2
• Measure of change in signal-to-noise for
population difference: ={1+/(1- 2)}/C
• Generalizability probability: replace  in power by
T(x)
Recommendation Based on
Generalizability Probability
Example
• A schizophrenia study
• 104 patients: 56 patients using new
treatment and 48 patients for standard
therapy
• T=-2.88 and p-value=0.004
• Reproducibility probability=0.814 > 80%,
thus a bridging trial is required
• =0.9 and desired power=80%, then n=118
Generalizability Probability and
Sample Size Requirement
Comments on Reproducibility
and Generalizability Probability
• Regulatory requirement of reproducibility and
generalizability probability are subjective.
• Need to know the population mean and variance
for new region
• Sample size of the bridging trial is larger than that
of original trial if <1
• Fail to address the similarity between the new and
original regions required by ICH E5 (Liu, et. at.
2002)
3rd Statistical Approach: Noninferiority or Equivalent Trial (1)
• “Sample size requirement for evaluation of
bridging evidence” by Liu, et. al. (2002)
Non-inferiority or Equivalent
Trial (2)
• Definition of Similarity: no substantial difference
(equivalence)
• Purpose: issue on sample size in planning bridging
study and evaluation of similarity
• Hierarchical model: trials have been conducted for
the approval of the drug product in original region
and a bridging trial is being conducted in a new
region for registration after the approval in the
original region
Example
Non-inferiority or Equivalent
Trial (4)
• What is the definition of similarity stated in ICH
E5?
• How to choose the margin?
• Comments in ICSA (2002)
• Controversial selection of equivalence limit
(Temple and Ellenberg (2000), Ellenber and
Temple (2000), Fisher et al. (2001), Hung (2001),
Snappin (2001), Tsong, et. al. (2001), Wittes (2001)
th
4
Statistical Approach: Baysian
Approach (1)
• Proposed by Shih in 2001 in Controlled
Clinical Trials
Baysian Approach (2)
• k study centers
• wi stands for test statistic i=1,…,k
• wi approximately follows N(μ,1) for large
sample size
• Predictive probability density function can
be obtained with vague prior for μ
• New trial is consistent with reference
studies if p(v|w)>min{p(wi|W), i=1,…,k}
Comments on Baysian Approach
(3)
• Correction is needed for small sample in a
particular center
• More reference studies, greater chance to be
consistent
5th Statistical Approach:
Multinational Trial (1)
Spilker in 1991 outlined the motivations of
conducting a multinational trial
1. Gaining more rapid patient enrollment
2. Expediting the development of a new medicine
3. Conducting a trial that otherwise might be
impossible
4. Gaining experience and being able to compare
patients of different nationalities
Takeuchi (2002) also raise the issues of the
importance in global drug development
Multinational Trial (2)
•
•
•
•
•
H0: 1-2=0
Ti represents for the test statistic where i=1,…,r
Tl represents for the test statistic for local region
Goal: check Tl to see if it is an outlier (not similar).
If it exists, then the ethnic difference is appeared.
-4
-2
0
2
x
4
0.0
0.1
0.2
density
0.3
0.4
If Ethnic Difference Exists
• A clinical trial is essentially required to
prove the effectiveness of study drug in the
local region (adjust the dose if needed)
• ICH E5: avoid unnecessary repetition of
costly and time-consuming clinical trials
(sample size reduction)
Dose Adjustment
Asian
Caucasian
AUC or Cmax
Dose
Sample Size Reduction
• “Sample Size Reduction in Bridging Study
Using Regression Estimator” by Wu et. al.
(2001)
Sample Size Reduction (2)
Sample Size Reduction (3)
Sample Size Reduction (4)
• Means, S.D. and slope need to know from
previous study in order to calculate the
sample size
• Interim analysis may be needed to reestimate means, S.D. and slope
Example
•
•
•
•
•
Acute Asthma study
Primary endpoint: FEV1
Compare study drug and placebo
Mean difference: 0.10 L
S.D.=0.31
Conclusions
• Under process to develop the statistical
approaches in CDE to detect the ethnic
sensitivity other than assessing PK/PD
profile
• Dose adjustment may be needed if ethnic
difference does exist
• Reducing sample size is considered if a
bridging trial is needed