Download Bridging Studies

1
An Overview of Bridging
Evaluations in Taiwan
Chin-Fu Hsiao1, Mey Wang2, Herng-Der Chen2,
Yu-Yi Hsu1 and Jen-pei Liu3
1
Division of Biostatistics and Bioinformatics
National Health Research Institutes
Zhunan, Taiwan
2Center
3Division
for Drug Evaluation, Taipei, Taiwan
of Biometry, Department of Agronomy
National Taiwan University
Taipei, Taiwan
2
Outline
 Introduction
 Taiwan’s Situations
 An Bayesian Approach
 Discussion
3
Introduction
ICH (International Conference on
Harmonisation) 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.
4
Ethnic Difference?
Targeted Clinical Trials and EGFR(Epidermal
growth factor receptor)
• Iressa (gefitnib) and Tarceva (Erlotinib) are
targted at the EGFR pathway.
• Efficacy is correlated to
race
number of gene copies
protein expression
EGFR mutation
Gappuzzo et al. (JNCI, 2005), Tsao, et al (NEJM, 2005)
5
Ethnic Difference?
Patients surviving (%)
—— IRESSA®
------ Placebo
1.0
1.0
1.0
0.9
0.9
Asian (n = 342)
0.9
HR = 0.66 (0.48, 0.91), P = .011
0.8
0.8
0.8
RR = 12.0%
0.7
0.7
0.6
0.5
0.5
0.5
0.4
0.4
0.4
0.3
0.3
0.3
0.2
0.2
0.2
0.1
0.1
0.1
0 0 11 22 33 44 55
RR = 6.5%
0.7
0.6
0.6
0.0
0.0
Non-Asian (n = 1350)
HR = 0.93 (0.81, 1.08), P = .364
0.0
6
7
8
9
10
11
12
13
14
6 7 8 9 10 11 12 13 14 15 1500 11
22 33
Time, mo
44 55
6 77 88 99 10
10 11
1112
12 13
1314
14 15
15
6
6
Objectives of ICH E5
 To describe the characteristics of foreign clinical data that
will facilitate their extrapolation to different populations
and support their acceptance as a basis for registration of 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
7
Bridging Data Package
A bridging data package consists of
1) Selected information from the complete clinical
data package (CCDP) that is relevant to the
population of the new region, including
pharmacokinetic data, and any preliminary
pharmacodynamic and dose-response data,
and
2) If needed, a bridging study to extrapolate the
foreign efficacy and/or safety data to the new
region.
8
Complete Clinical Data
Package
A clinical data package intended for
registration containing clinical data that fulfill the
regulatory requirements of the new region and
containing pharmacokinetic data relevant to the
population in the new region
9
Bridging Study
A bridging study is defined as a supplemental 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 new region.
10
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).
11
Ethnic Factors
 Intrinsic Ethnic Factors are more genetic and
physiologic in nature
e.g., genetic polymorphism, age, gender, height,
weight, lean body mass, body composition, and
disease conditions, etc.
 Extrinsic Ethnic Factors are more social and
cultural in nature
e.g., environment, culture, medical practice, health
insurance, practices in clinical trials or conduct
12
Bridging Studies
• ICH E5
• Only after the medicine is approved in
the original region
• Performed in the new region
13
No Need to Bridge
• Ethnically insensitive medicine:
Similar medical practice and conduct of
clinical trials
• Ethnically sensitive medicine:
Ethnically similar regions and sufficient
clinical experience.
14
What to Bridge?
• Data from the new region
Pharmacodynamic, efficacy, safety, dosage,
dose regimen
• Ability to extrapolate to new region
Similar in dose response, efficacy, safety
either with the same doses or with dose
adjustment.
15
Taiwan’s Situations
16
Taiwan Before Bridging Study
 An approved local clinical trial study report is
required for the new drug application in
Taiwan—July 7 Announcement in 1993
Disadvantage:
 A sample size of 40 as required would be
difficult to demonstrate significant importance
clinically or statistically
 The study design of the local trial usually only
repeated a study that has been done in the foreign
countries but in a smaller sample size;The study
has not been designed based on the medical
situation in Taiwan
17
Taiwan’s Strategy to Implement
Bridging Study
 Smoothly convert compulsory Local Clinical Trial (LCT) to
meaningful bridging study
 Gradually, stepwise announce waived local clinical trial
 Create an environment: (1) meet international regulation,
ICH
(2) require optimized dosage for
Taiwanese patient
 Communicate with local and international pharmaceutical
industry
 Announce new regulation according to the international
norm and the consensus from communications
 Create an international platform “APEC – Taipei”
 Implement Double Twelve Announcement – Bridging
Study
18
Stepwise Implementation
 1998 Announce: two years later, switch from LCT to
bridging study
 Many communications and negotiations with local and
international pharmaceutical industry
 2000, Dec.12, (Double Twelve Announcement) – public
announce bridging study regulation
 1998 Five announcements of LCT wavier
 Two years transition periods: both LCT and bridging
studies acceptable from 2000 ~ 2002
 Many international conferences held in Taipei and other
Asian countries, regarding BS, through the APEC platform
 Ask CDE to complete the practical issues related to
implementation of BS
 2004, Jan. 1, Bridging evaluation
19
Available Statistical Methods
1. Hierarchical Model
(Liu, Hsueh, and Chen, 2002, Biometrical Journal,
44: 969-981)
2. Takeuchi, M. Controlled Clinical Trials 23: 55-57, 2002
3. Shao, J. and Chow, S. C. Statistics in Medicine, 21:
1727-1742, 2002
4. Population Similarity
(Chow, Shao, Hu, 2002, JBS, 12: 385-400)
5. Consistency Approach
(Shih, 2001, Controlled Clinical Trials, 22: 357-366)
6. Bayesian Positive Treatment Approach
(Liu, Hsiao, and Hsueh, 2002, JBS 12: 297-294)
7. Bayesian Noninferiority Approach
(Liu, Hsueh and Hsiao, 2004, JBS accepted)
8. Group Sequential Approach
(Hsiao, Xu and Liu, 2003, JBS, 13: 793-801)
9. Two-Stage Approach
(Hsiao, Xu and Liu, 2004, submitted)
20
Products Requiring No Verification of
Ethnic Insensitivity







Drugs for treatment of AIDS
Drugs for organ transplantation
Topical agents
Nutrition supplements
Cathartics prior to surgery
Radiolabelled diagnostic pharmaceuticals
The drug is the only choice of treatment for a given
severe disease
 Drugs for life-threatening disease have
demonstrated a breakthrough efficacy
 Lacking adequate trial subjects for any drug used
for rare disease
21
Products Requiring Verification of
Ethnic Insensitivity








Anticancer drugs
Drugs with breakthrough efficacy
Drugs of single use
Drugs with different salt of the same composition and the
same administered route have been approved internal
Drugs for chronic psychologic or immunological diseases
and conducting clinical trails internal difficultly
Each compounds of new combination drug have been
proved internal, and the efficacy is the same as the single
compound
Drugs with the mechanism, administered route, efficacy
and adverse effect, similar to the approved drugs
New combination composed of single compound of
approved combination or compounds of approved
combination has the same efficacy as approved
combination
Checking List for Sponsors (1 of 3)
Checking List for the evaluation of Bridging Study by the Sponsor
INFO
Data Package
Y3 N
Vol., page1
I. The current status of clinical study of the drug in the world
□□
II. NDA expert report or Investigator’s Brochure2
□□
III. Pharmacokinetics, safety and efficacy data related to Asian population
□□
IV.Comparative analysis of Pharmacokinetics, safety and efficacy data
between Asian population and others.
□□
V. Self evaluation (please provide reference materials or literature)
Y N U
□□
□□□
□□
2. Is the drug with a steep pharmacodynamic curve for both efficacy
and safety (a small change in dose results in a large change in
□□□
effect) in the range of the recommended dosage and dose
regimen?
□□
□□□
□□
1. Does the drug show a Non-linear pharmacokinetics at the
therapeutic dose?
3. Is the drug with narrow therapeutic dose range?
Note：
1. To speed up reviewing process, please clearly indicate the volume and page number as requested. In
addition to the page number, the related paragraph may be highlighted when necessary.
2. Please provide the comparative analysis of different ethnic groups, if it’s available. Please also explain
if there is no comparative analysis of different ethnic groups in NDA expert report.
3. Y=yes; N=no; U=unknown
22
23
Checking List For Sponsors (2 of 3)
Checking List for the evaluation of Bridging Study by the Sponsor
V. Self evaluation (please provide reference materials or literature)
4. Is the drug highly metabolized, especially through a single
pathway, thereby increasing the potential for drug-drug
interaction ?
5. Is the drug metabolized by enzyme known to show genetic
polymorphism?
INFO
Data Package
Y2 N
Vol., page1
Y N U
□□
□□□
□□
□□□
□□
6.
Is the drug administered as a prodrug, with the potential for
ethnically variable enzymatic conversion ?
□□□
□□
7.
Is the drug with high inter-subject variation in bioavailability ?
□□□
□□
8.
Is the drug with low bioavailability, thus more susceptible to
dietary absorption effects?
□□□
□□
9.
Is the drug with high likelihood of use in setting of multiple comedications ?
□□□
□□
□□□
□□
10. Is the drug with high likelihood for inappropriate use, e.g.
analgesics and tranquilizers ?
Note：
1.
To speed up reviewing process, please clearly indicate the volume and page number as requested. In
addition to the page number, the related paragraph may be highlighted when necessary.
2.
Y=yes; N=no; U=unknown
Checking List for Sponsors (3 of 3)
Checking List for the evaluation of Bridging Study by the Sponsor
V. Self evaluation (please provide reference materials or literature)
INFO
Data Package
Y3 N
Vol., page1
Y N U
□□
11. Is there any difference in epidemics of applied indication between
the major study population and our population (including medical
□□□
history, mechanism of disease development and the rate of
occurrence, the efficacy and safety of other drugs in the same
class)?
□□
12. Other important ethnic sensitive factors, such as “Is there any
difference in the medical practice?”
□□
□□□
VI. Post-marketing surveillance information
□□
Overall conclusion of self evaluation (Is it clinically insignificant? What
is the risk and benefit of the drug applied (such as, “Does the indication
applied belong to severe disease”, “Is there a alternative therapy?”, “Are
the differences of the data in ethnic factors acceptable ?)
□□
Summary3
□□
Note：
1. To speed up reviewing process, please clearly indicate the volume and page number as requested. In
addition to the page number, the related paragraph may be highlighted when necessary.
2. Y=yes; N=no; U=unknown
3. Please according the checking list provide an integrate summary or a brief description of all the
information submitted.
24
25
Sponsor
•Bridging Data Package
•Summary for the
Consideration of Bridging
Study
BoPA
Accept
submission
Checking List
Expert Consultants
(Statistical, Clinical,
Pharmacokinetics
reviewers)
CDE
CDE acceptance
verification
Technical Review
(Designate
reviewer)
Review meeting
Schedule Sponsor
meeting
Supplement
Result of Evaluation:
1. No Bridging study
required
2. Bridging study is required
– Type of Bridging study
Sponsor meeting
Clinical Review
Committee
Notification
Review report and
Recommendation:
1. No Bridging
study required
2. Bridging study is
required – Type of
Bridging study
26
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28
Does bridging strategy of ICH E5 warrant
further implementation?
Is Taiwan on the right way?
29
Case I
 Drug A is a fixed combination of 200mg
dipyridamole/25mg aspirin 1bid for prevention of
recurrent stroke
 After the standard process of BSE, we decided to
request a bridging study due to an ethnic
difference in medical practice (much lower dose
for one of the components in Taiwan) and higher
headache-associated dropout rate in previous
Philippine study
30
Case I
 Headache drop out rate: Phillipino > Caucasian
 Local Bridging Study Result : first 4 weeks
Group
Placebo
Reduced Dose 2wk
Full Dose
Full Dose 2wk
4wk
Headache
8.7%
6.7%
16.3%
drop out rate
 Risk Management: Change labeling’s instruction for use
31
Case II
 Drug B is a new potent lipid-lowering agent
 The PK study in Japanese shows that Cmax
of Japanese is 1.9~2.5 times of that for
Caucasian while AUC is 2~2.5 times
 Although the mean interracial difference is
not substantial, Taiwan approved the drug
with reduced maximal dosage due to the
dose-dependent, drug-related rare SAE of
rhabdomyolysis
32
Case II
 The decision is further echoed by US FDA
 After reviewing the results of a Phase IV
PK study in Asian-Americans, FDA urged
the physician to reduce the starting dose and
prescribe high dose with caution for Asians
in Labeling in March, 2005
33
Bayesian Approach
34
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
35
Assumption, Notation and
Hypotheses
 We focus on the trials for comparing a test product
and a placebo control
 Xi and Yj are some efficacy responses for patients i
and j receiving the test product and the placebo
control respectively in the new region
 Xi’s and Yj’s are normally distributed with known
variance σ2
 μNT and μNP are the population means of the test
and placebo, respectively, and let ΔN = μNT - μNP
 H0: ΔN  0 vs. HA: ΔN > 0
36
Use of Prior distribution
The proposed mixture model of the prior
distribution for ΔN is a weighted average of
the noninformative and normal priors as given
below
π(ΔN) =γπ1(ΔN) + (1-γ)π2(ΔN)
 π1(.) ≡c is a non-informative prior
 π2(.) is a normal prior with mean θ0 and variance
σ02 which summarizes the foreign clinical data
about the treatment difference provided in the
CCDP
 0≦γ≦1
37
Marginal Density
Based on the clinical responses from the
bridging study in new region, ΔN can be
estimated by
ˆ x y .

N
N
N
The marginal density is
 (ˆ N   0 ) 2 
m(ˆ N )    (1   )
exp 
,

2
2
~
 2( 0   ) 
2 ( 02  ~ 2 )
1
where
~ 2   2 / nT   2 / nP .
38
Posterior Distribution
Given the bridging data and prior distribution,
the posterior distribution of ΔN is
1
ˆ
 ( N |  N ) 
m(ˆ


) 
 ( N  ˆ N ) 2 
exp 

2
~
~
2
2 


1
2
2 
ˆ


(



)
(



)
1
N
0
N
N
(1   )
exp 

 .
2
2
~
~
2 0
2
2  0

 
39
Bridging Evaluation
Similarity on efficacy in terms of a positive
treatment effect for the new region can be
concluded if the posterior probability of
Similarity
PSP  P(  NT   NP  0 | bridging data and prior )

   ( N | ˆ N )d N
0
 1,
for some pre-specified 0 <  < 0.5.
40
Example
 The CCDP provides the results of three
randomized, placebo controlled trials for a
new antidepressant (test drug) conducted in
the original region
 The primary endpoint is the change from
baseline of sitting diastolic blood pressure
(mmHg) at week 12
 A bridging study was conducted in the new
region to compare the difference in efficacy
between the new and original region
41
Three Scenarios
 The first scenario presents the situation where no
statistically significant difference in the primary
endpoint exists between the test drug and placebo (2sided p-value = 0.6430
 The second situation is that the mean reduction of
sitting diastolic blood pressure at week 12 of the test
drug is statistically significantly greater than the
placebo group (2-sided p-value < 0.0001)
 The third scenario is the situation where due to the
insufficient sample size of the bridging study, no
statistical significance is found between the test drug
and placebo although the magnitude of the difference
between the test drug and placebo observed in the
original region is preserved in the new region (2-sided
p-value = 0.0716)
Region
Statistics
42
Treatment Group
Drug
Placebo
N
138
132
Mean
-18
-3
Standard Deviation
11
12
N
185
179
Mean
-17
-2
Standard Deviation
10
11
N
141
143
Mean
-15
-5
Standard Deviation
13
14
New 1
N
64
65
(Example 1)
Mean
-4.7
-3.8
Standard Deviation
11
11
New 2
N
64
65
(Example 2)
Mean
-15
-2
Standard Deviation
11
11
New 3
N
24
23
(Example 3)
Mean
-11
-4
Standard Deviation
13
13
Original 1
Original 2
Original 3
43

0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Example 1
1.0000
0.6789
0.6789
0.6789
0.6789
0.6789
0.6789
0.6789
0.6789
0.6789
0.6789
Psp
Example 2
1.0000
0.9999
0.9999
0.9999
0.9999
0.9999
0.9999
0.9999
0.9999
0.9999
0.9999
Example 3
1.0000
0.9727
0.9700
0.9690
0.9685
0.9682
0.9680
0.9678
0.9677
0.9676
0.9675
44
Scenario I
 If the regulatory agency allows all
information of the original region to be used
for evaluation of similarity between the new
and original region, γ is set to be 0 and
hence PSP 1.00
 If γ ≧ 0.1, then PSP always drops to around
0.6789
45
Scenario II
 The values of PSP in Example 2 appear to be
close to 1.00 regardless of the choice of γ
46
Scenario III
• The values of PSP are all greater than 0.9675 for all
values of γ between 0 and 1
• With the strength of the substantial evidence of
efficacy is borrowed from the CCDP of the
original region, our procedure can prove the
similarity of efficacy between the new and original
region when a non-significant efficacy result but
with a similar magnitude is observed in the
bridging study
47
Final Remarks
 The proposed prior is a weighted average of a
non-informative prior and a normal prior
 The proposed procedure can avoid the situation of
concluding similarity between the new and
original region when the efficacy result of the test
drug observed the bridging study of the new
region is same as or even worse than that of the
placebo group
 Our proposed procedure can reach a conclusion
that is more consistent with the results obtained
from the bridging study
48
Final Remarks
 Selection of weight γ by the regulatory
agency in the new region should consider
all differences in both intrinsic and extrinsic
ethnical factors between the new and
original regions and at the same time should
also reflect their belief on the evidence of
efficacy provided in the CCDP of the
original region
49
Final Remarks
 We use a normal prior for summarization of
the results in CCDP of the original region
 We also use other prior distributions
I) double exponential distribution
II) lognormal distribution
 Other different distributions used for π2
reach the same conclusion
50
Thanks for your attention!