1 chapter 9 bridging studies. 2 outline introduction taiwan ’ s situations an bayesian approach...
TRANSCRIPT
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.
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Asian (n = 342)HR = 0.66 (0.48, 0.91), P = .011
RR = 12.0%
Non-Asian (n = 1350)HR = 0.93 (0.81, 1.08), P = .364
RR = 6.5%
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—— IRESSA®
------ Placebo
Time, mo
Pat
ien
ts s
urv
ivin
g (
%)
Ethnic Difference
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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
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Bridging Data PackageA 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.
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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
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Bridging StudyA 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.
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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
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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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Taiwan’s Situations
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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
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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
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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
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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)
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INFO
Y3 N
Data Package
Vol., page1 Checking List for the evaluation of Bridging Study by the Sponsor
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
1. Does the drug show a Non-linear pharmacokinetics at the therapeutic dose?
□ □□ □ □
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?
□ □□ □ □
□ □□ □ □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
Checking List for Sponsors (1 of 3)
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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
INFO
Y2 N
Data Package
Vol., page1 Checking List for the evaluation of Bridging Study by the Sponsor
V. Self evaluation (please provide reference materials or literature) □ □Y N U
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?
□ □□ □ □
□ □□ □ □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 co-medications ?
□ □□ □ □10. Is the drug with high likelihood for inappropriate use, e.g. analgesics and tranquilizers ?
Checking List For Sponsors (2 of 3)
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INFO
Y3 N
Data Package
Vol., page1 Checking List for the evaluation of Bridging Study by the Sponsor
V. Self evaluation (please provide reference materials or literature) □ □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?” □ □□ □ □
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=unknown3. Please according the checking list provide an integrate summary or a brief description of all the
information submitted.
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 □ □
Checking List for Sponsors (3 of 3)
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•Bridging Data Package•Summary for the Consideration of Bridging Study
Accept submission
Checking ListTechnical Review
(Designate reviewer)
Review meeting
Sponsor meetingSupplement
Clinical Review Committee
Review report and Recommendation:1. No Bridging study required2. Bridging study is required – Type of Bridging study
Result of Evaluation:1. No Bridging study
required2. Bridging study is required
– Type of Bridging studyNotification
Sponsor BoPA CDE
CDE acceptance
verification
Expert Consultants (Statistical, Clinical, Pharmacokinetics reviewers)
Schedule Sponsor meeting
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71.1
21.1 21.1 21.1
47.455.3
5.3
31.6
2.6
0
20
40
60
80
100R
easo
ns f
or n
ot w
aive
d/to
tal c
ases
(%
)
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Does bridging strategy of ICH E5 warrant further implementation?
Is Taiwan on the right way?
23
Case I
Drug A is a fixed combination of two anti-platelet agents with indication for secondary prevention of thromboembolic stroke (200mg dipyridamole/25mg aspirin 1bid)
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
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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
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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
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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
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Bayesian Approach
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Bayesian ApproachFor 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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Before Experiment
After Experiment
Bayesian Approach
Past experience about similar situations
involving similar
Prior informationP (
Posterior information
P(prior&data
Observed results( Data )
MakeStatisticalinference
Treatmenteffect
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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
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Parameters
Test Product Effect
Placebo Effect
Original Region OT OP
New Region NT NP
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Before Bridging Study
Original region data to estimate OT
Original region data to estimate OP
ConcludeOT > OP
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Bayesian Positive Treatment Approach
Original region information to
form prior
Posterior information
P{NT-NP prior & bridging
Bridging data
New regiontreatment effect
NT — NP
Conclude NT>NP if
P{NT-NP>0 prior & bridging
is large
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Previous Statistical Approach
Use the estimate of treatment effect from the original region formulated as a normal prior
Compute the posterior treatment effect with the data from the new region
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Results from Original RegionChange from baseline in sitting DBP at week 12Region Statistics Test PlaceboI n 138 132
Mean -18 -3 SD 11 12
II n 185 179 Mean -17 -2
SD 10 11III n 141 143
Mean -15 -5 SD 13 14
Previous Statistical Approach
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Results from New Region:
Change from baseline in Sitting DBP at week 12
Region Statistics Test PlaceboNew n 64 65
Mean -4.5 -3.8 SD 11 11
Posterior probability of similarity: Psp 1
Previous Statistical Approach
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Previous Statistical Approach
Original region: Efficacy of the test drug is superior to the placebo
New Region: Reduction of sitting BP of the test drug is same as that of the placebo
Conclusion: The results of the original region can be extrapolated to the new region despite of inconsistent results between original and new regions
Evaluation of bridging studies is overwhelmingly by the results of original region due to imbalance of information provided by the two regions
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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 σ
02 which summarizes the foreign clinical data abou
t the treatment difference provided in the CCDP 0 γ 1≦ ≦
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Marginal Density
Based on the clinical responses from the
bridging study in new region, ΔN can be
estimated by
The marginal density is
where
.ˆNNN yx
,)~(2
)ˆ(exp
)~(2
1)1()ˆ(
220
20N
220
N
m
.//~P
2T
22 nn
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Posterior Distribution
Given the bridging data and prior distribution,
the posterior distribution of ΔN is
.~2
)ˆ(
2
)(exp~2
1)1(
~2
)ˆ(exp~2
1
)ˆ(
1)ˆ|(
2
2NN
20
20N
0
2
2NN
NN
m
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Bridging EvaluationSimilarity on efficacy in terms of a positivetreatment effect for the new region can beconcluded if the posterior probability ofSimilarity
for some pre-specified 0 < < 0.5.
,1
)ˆ|(
)prior and data bridging|0(PP
0
NNN
NPNTSP
d
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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
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Three Scenarios The first scenario presents the situation where no
statistically significant difference in the primary endpoint exists between the test drug and placebo (2-sided 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)
44Treatment Group Region Statistics
Drug Placebo
Original 1 N
Mean
Standard Deviation
138
-18
11
132
-3
12
Original 2 N
Mean
Standard Deviation
185
-17
10
179
-2
11
Original 3 N
Mean
Standard Deviation
141
-15
13
143
-5
14
New 1
(Example 1)
N
Mean
Standard Deviation
64
-4.7
11
65
-3.8
11
New 2
(Example 2)
N
Mean
Standard Deviation
64
-15
11
65
-2
11
New 3
(Example 3)
N
Mean
Standard Deviation
24
-11
13
23
-4
13
45
Psp Example 1 Example 2 Example 3
0.0 1.0000 1.0000 1.0000 0.1 0.6789 0.9999 0.9727 0.2 0.6789 0.9999 0.9700 0.3 0.6789 0.9999 0.9690 0.4 0.6789 0.9999 0.9685 0.5 0.6789 0.9999 0.9682 0.6 0.6789 0.9999 0.9680 0.7 0.6789 0.9999 0.9678 0.8 0.6789 0.9999 0.9677 0.9 0.6789 0.9999 0.9676 1.0 0.6789 0.9999 0.9675
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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 P≧ SP always drops to around
0.6789
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Scenario II
The values of PSP in Example 2 appear to be
close to 1.00 regardless of the choice of γ
48
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
49
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
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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
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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