1

An Overview of Bridging EvaluaAn Overview of Bridging Evalua

tions in Taiwantions in Taiwan

Chin-Fu HsiaoChin-Fu Hsiao11, Mey Wang, Mey Wang22, Herng-Der Chen, Herng-Der Chen22, Y, Yu-Yi Hsuu-Yi Hsu11 and Jen-pei Liu and Jen-pei Liu33

11 Division of Biostatistics and BioinformaticsDivision of Biostatistics and Bioinformatics

National Health Research InstitutesNational Health Research Institutes

Zhunan, TaiwanZhunan, Taiwan22Center for Drug Evaluation, Taipei, TaiwanCenter for Drug Evaluation, Taipei, Taiwan

3Division of Biometry, Department of Agronomy

National Taiwan UniversityNational Taiwan University

Taipei, TaiwanTaipei, 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

Targeted Clinical Trials and EGFR(Epidermal growth factor receptor)

• Iressa (gefitnib) and Tarceva (Erlotinib) are targted at the EGFR pathway.

• Efficacy is correlated toracenumber of gene copies

protein expression EGFR mutation Gappuzzo et al. (JNCI, 2005), Tsao, et al (NEJM, 2005)

Ethnic Difference?

5

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 150.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15

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%

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.00 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15

—— IRESSA®

------ Placebo

Time, mo

Pat

ien

ts s

urv

ivin

g (

%)

Ethnic Difference?

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 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.

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 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.

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 r

equired 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 bridgi

ng study Many communications and negotiations with local and inte

rnational pharmaceutical industry 2000, Dec.12, (Double Twelve Announcement) – public an

nounce bridging study regulation 1998 Five announcements of LCT wavier Two years transition periods: both LCT and bridging studie

s acceptable from 2000 ~ 2002 Many international conferences held in Taipei and other A

sian countries, regarding BS, through the APEC platform Ask CDE to complete the practical issues related to imple

mentation 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 demonstrat

ed a breakthrough efficacy Lacking adequate trial subjects for any drug used f

or 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 s

ame administered route have been approved internal Drugs for chronic psychologic or immunological diseases a

nd conducting clinical trails internal difficultly Each compounds of new combination drug have been prov

ed 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

22

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)

23

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)

24

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)

25

•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

26

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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

(%

)

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 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

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 σ

02 which summarizes the foreign clinical data abou

t 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

The marginal density is

where

.ˆNNN yx

,)~(2

)ˆ(exp

)~(2

1)1()ˆ(

220

20N

220

N

m

.//~P

2T

22 nn

38

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

39

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

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 (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)

42Treatment 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

43

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

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 P≧ SP 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!