Download powerpoint

Experience in Korea on
Bridging Studies
In-Jin Jang M.D., Ph.D.
Clinical Pharmacology Unit, Clinical Trial Center
Seoul National University Hospital (SNUH) &
Seoul National University College of Medicine
SNUH-CTC

1999



Recent Changes in Korean
Regulations for Clinical Trials
Elimination of compulsory conduction of local clinical trial in Korea
as a condition of registration (For the products with < 3yr market
experience or, For the products only marketed in the original
developing country)
 Introduction of Bridging Study System; Dec. 1999
 Bridging study waiver until June 2001
Allowance for conducting the multi-national, multi-center trials
2002


Separation of IND system and NDA system.
Began to collect user-fee but not providing consultation about the
clinical trial designs yet.
Bridging Data Generation :
Experiences in Korea (1)
SNUH-CTC

Track for “marketing approval without
domestic/Korean bridging data”;  8 drugs





1 for life-threatening condition,
4 orphan drugs,
1 diagnostic,
1 topical drug,
1 antibiotic without domestic/Korean clinical data


on the basis of ethnic insensitivity and in vitro microbiological
sensitivity test of domestic clinical isolates
2 failed to register without domestic bridging data

Insulin analogue and one more endocrine drug
SNUH-CTC

Bridging Data Generation :
Experiences in Korea (2)
Track for single pharmacokinetic study for
bridging data generation;  11 drugs

Three products were approved with single Korean
pharmacokinetic clinical trial data.



Three sponsors finished PK studies


Actos, Avandia, Gastrointestinal (GI) drug
GI drug study was done in Koreans living in an other country
ED, IBS, antimuscarinic
More than 5 sponsors are planning to do PK based
bridging data generation

BPH/alopecia, diuretic, vascular, antihyperlipidemic,
hormonal agent
SNUH-CTC

Bridging Data Generation :
Experiences in Korea (3)
Track for phase 3 clinical study for bridging
data ;  11 drugs, (12 indications)





None approved yet
Open trial: 3, Blinded trial: 9
Placebo control: 2, Active control: 7
Sample size: 30 (open) ~ 284 (142 x 2)
Therapeutic class

Analgesics (1), Antibiotic (1), Erectile dysfunction (1),
Endocrine (3), Glaucoma (1), Antipsychotic (1),
Respiratory (1), Rheumatic (2)
SNUH-CTC

Bridging Data Generation :
Experiences in Korea (4)
Multi-national phase 2/3 clinical study for
bridging data ;  19 drugs, (23 trials)





None approved yet
Open trial: 7, Blinded: 12
Placebo control: 8, Active control: 12
Sample size: 16, 30/630, 98, 20/700, etc.
Therapeutic class

Antibiotic (3), Anticancer (7), Antifungal (1),
Antihypertensive (2), Antiviral (2), ED (1),
Dementia (1), Gastrointestinal (2), Osteoporosis (2),
Thrombolytic (1), CNS (1)
Pharmacokinetics of XX prolonged release
capsules in Japanese, Caucasian and Korean
healthy volunteers, with a tolerability
assessment in the Japanese subjects.
A multiple-dose, placebo-controlled sequential
dose-escalation study
Clinical Trial Center / Clinical Pharmacology Unit
Seoul National University Hospital
(SNUH)
Study Summary
SNUH-CTC

Objectives: show similarity in steady state AUC for the active
moiety (sum of the unbound parent drug and metabolite1) between
Japanese versus Caucasians and Japanese versus Korean subjects

Study design:




Parallel group
Age/weight matching of the Caucasian and Korean groups to
Japanese
Single-dose and 5-day multiple dose administration
Dosage and subjects
Japanese
Caucasian
Korean
Placebo
Active
Active
12
3
12
12
2x mg
12
3
12
12
3x mg
12
3
12
12
Treatment
definition
Active
x mg
SNUH-CTC
Point estimate and 90 % C.I. for AUC0-
ratios in Japanese/Caucasian
Substance
Period
Ratio
90 C.I.
Lower
bound
90 C.I.
Upper
bound
Active (M1+P)
Day 1 incl. outliers
0.91
0.80
1.03
Metabolite1
Day 1
0.93
0.82
1.05
Parent drug
Day 1 incl. outliers
0.77
0.50
1.18
Substance
Period
Ratio
90 C.I.
Lower
bound
90 C.I.
Upper
bound
Active (M1+P)
Day 7 incl. outliers
0.90
0.78
1.03
Metabolite1
Day 7 incl. outliers
0.84
0.71
0.98
Parent drug
Day 7 incl. outliers
0.80
0.51
1.26
SNUH-CTC
Point estimate and 90 % C.I. for AUC0-24
ratios in Japanese/Korean
Substance
Period
Ratio
90 C.I.
Lower
bound
90 C.I.
Upper
bound
Active (M1+P)
Day 1 incl. outliers
0.77
0.67
0.89
Metabolite1
Day 1 incl. outliers
0.81
0.72
0.92
Parent drug
Day 1 incl. outliers
0.50
0.39
0.65
Substance
Period
Ratio
90 C.I.
Lower
bound
90 C.I.
Upper
bound
Active (M1+P)
Day 7 incl. outliers
0.72
0.62
0.83
Metabolite
Day 7 incl. outliers
0.70
0.59
0.82
Parent drug
Day 7 incl. outliers
0.52
0.39
0.70
Phase I Study of YY, Placebo-controlled, Doubleblind, Group-comparison, Dose-escalation study
to Investigate Safety, Tolerability, and
Pharmacokinetics after Single Oral Dosing of
5mg, 10mg and 20mg in Healthy Subjects
In-Jin Jang M.D., Ph.D.
Clinical Pharmacology Unit /Clinical Trial Center
Seoul National University Hospital (SNUH)
SNUH-CTC

Study design



Study Summary
Placebo-controlled, single ascending dose, parallel
group
Double-blind, randomized study
Dosage and subjects
Steps
1
Dosage
5 mg
2
10 mg
3
20 mg
Number of Subject
Drugs
8
Active, 5mg tablet
2
Placebo, 5mg tablet
8
Active, 10mg tablet
2
Placebo, 10mg tablet
8
Active, 20mg tablet
2
Placebo, 20mg tablet
SNUH-CTC
Pharmacokinetics
Plasma Drug concentration (ug/L)
100
5 mg (n=8)
10 mg (n=8)
20 mg (n=8)
Geometric mean; Geometric SD
10
1
0.1
0
4
8
12
16
20
24
Time after administration (hr)
Plasma concentration profiles of Study Drug after single oral dosing of 5, 10 and 20
mg under fasting condition
SNUH-CTC
Korean vs. Caucasian
Study
Number
Race
000
000
Korean
Caucasian
(n=8)
(n=8)
(n=8)
(n=24)
(n=24)
Dose (mg)
5
10
20
10
20
Tmax (h) b
0.5
(0.5~0.75)
0.5
(0.5~0.75)
0.5
(0.5~1.0)
0.884
(0.50~1.5)
0.992
(0.48~1.5)
Cmax (㎍/L)
9.70/1.40
17.14/1.76
41.55/2.19
7.03/1.73
18.5/1.52
AUC
(㎍*h/L)
17.92/1.41
35.26/1.65
93.49/1.88
28.8/1.62
70.0/1.53
T 1/2 (h)
3.49/1.44
3.31/1.32
3.51/1.33
4.76/1.51
4.80/1.36
Vz/F (L/kg)
21.54/1.61
19.78/1.57
16.63/1.56
29.6/1.77
24.6/1.50
CL/F (L/h)
278.9/1.41
283.6/1.65
213.9/1.88
347/1.62
286/1.53
SNUH-CTC
Korean vs. Caucasian
50
120
Korean
Caucasian
Korean
Caucasian
40
80
Cmax (ug/L)
AUC (ug*h/L)
100
60
40
30
20
10
20
0
0
5
10
15
Dose of Study Drug (mg)
20
5
10
15
Dose of Study Drug (mg)
20
Evaluation of Safety and
Pharmacokinetics of Single Dose
of Rosiglitazone in Healthy
Korean Volunteers
In-Jin Jang, MD, PhD
Clinical Trial Center / Clinical Pharmacology Unit
Seoul National University Hospital (SNUH)
SNUH-CTC
Point Estimates and 90% Confidence Intervals in Korean : Caucasian
Volunteers for AUC(0-inf) (ng.h/mL), Cmax (ng/mL), and T1/2 (h)
Endpoint
Comparison
AUC(0-inf)
K:W1
Cmax
K:W1
T1/2
K-W2
Dose
(mg)
2
4
8
2
4
8
2
4
8
Point
Estimate
1.48
1.48
1.61
1.36
1.37
1.37
1.41h
0.69h
0.86h
1 presented as the ratio of geometric means.
2 presented as the arithmetic mean difference
K
Korean Volunteers (each dose group : n= 8)
W
Caucasian Volunteers (2mg n=51;
4mg n=25;
8mg n=53)
90%
Confidence Interval
(1.25, 1.74)
(1.24, 1.77)
(1.36, 1.90)
(1.16, 1.60)
(1.15, 1.63)
(1.16, 1.60)
(0.82h, 2.00h)
(0.06h, 1.32h)
(0.27h, 1.44h)
SNUH-CTC
Pharmacokinetic parameters of Avandia in Caucasian and Korean
healthy subjects
Ratio (Korean/ Caucasian)
Equivtest
NONMEM
Geometric Mean
Pharmacokine
tic Parameters
Dose
normalized
AUCinf
(hrㆍng/mL)
Dose
normalized
Cmax
(ng/mL)
T1/2 (hr)
Korean
male
(n=24)
Caucasian
male
(n=79)
Point
Estimate
90% CI
Point
Estimate
512.77
344.21
1.49
1.38~1.61
1.47
90.13
68.03
1.32
1.22~1.42
1.29
4.56
3.63
1.25
1.13~1.35
1.29
SNUH-CTC
Pharmacokinetic parameters of Aisan and Caucasian healthy subjects
single-dose (4mg or 8mg) oral administration Rosiglitazone
Dose
Parameter
N
Cmax
ng/ml
4mg
AUC0-inf
h·ng/ml
T1/2
H
8mg
AUC0-inf
h·ng/ml
T1/2
H
Chinese
Taiwanese
Japanese Caucasian
8
12
12
6
25
Mean
345.3
445.86
384.1
326.90
260.2
SD
60
67.71
59.3
46.58
75.6
Ratio
1.33
1.7
1.47
1.25
1
Mean
1960
2177.8
2078
1724
1374
SD
525
506.8
433
335.16
545
Ratio
1.43
1.58
1.51
1.25
1
Mean
4.35
3.92
4.18
4.04
3.65
SD
1.020
0.75
0.43
0.39
1.08
Ratio
1.19
1.07
1.14
1.04
1
8
12
12
6
25
Mean
765.2
832.58
724.3
746.85
558.2
SD
185.22
170.96
135.7
147.37
127.5
Ratio
1.37
1.49
1.29
1.34
1
Mean
4508
4505
4024
3619
2792
SD
1342
959
956
573
660
Ratio
1.61
1.61
1.44
1.29
1
Mean
4.67
3.76
4.19
3.63
3.81
SD
0.64
0.61
0.57
0.42
0.93
N
Cmax
ng/ml
Korean
ACTOS®
PK/PD Modeling and
Simulation for Bridging
KFDA CPAC
2002.2.22
In-Jin Jang MD PhD
Clinical Trial Center/Clinical Pharmacology Unit
Seoul National University Hospital
SNUH-CTC
A Single Dose, Dose-Escalation Study to Assess the
Pharmacokinetic Characteristics and Safety/Tolerability of
Pioglitazone in Healthy Korean Subjects
Dose
Pioglitazone
Placebo
15 mg
30 mg
45 mg
6 Male + 3 Female
6 Male + 3 Female
6 Male + 3 Female
2 Male + 1 Female
2 Male + 1 Female
2 Male + 1 Female
Direct AUC Comparison
SNUH-CTC
Koreans vs. Western
40000
35000
AUC (ng hr/mL)
30000
25000
20000
15000
10000
5000
0
Korean 15 mg
Western 30 mg
Korean 30 mg
Western 45 mg
Predicted Glucose Response - AUC
Relationships in Korean Populations
SNUH-CTC
Glucose -AUC relationships
from Relationships
global data supports
AUC-Glucose Response
(Studies PNFP -001, -012, -026)
15 and 30 mg as efficacious doses in Koreans
Fasting Plasma Glucose (mg/dL)
Change from Baseline
0
Observed (mean & SE)
Fitted Curve
Korean mean AUC (15 mg)
Korean mean AUC (30 mg)
-20
-40
-46
-55
-60
max response ~ -72 mg/dL
-80
1000
10000
AUC (ng*hr/mL)
SNUH-CTC
Korean & US Combined PK by NONMEM
Parameter
Estimate StdErr %SE
--------- ------ ------ ---THETA #1 KA 2.50 0.883 35.32
THETA #2 CL 3.16 0.145 4.59
THETA #3 V2 29.3 1.29
4.40
THETA #4 orig -0.416 0.0403 9.69
OMEGA #1 CL 0.109 0.0151 13.85
SIGMA #1 - 0.181 0.0140 7.73
$PK
PJ=0
IF(PROJ .EQ. 7110115) PJ=1
KA=THETA(1)
TVCL=THETA(2)*(1 + PJ*THETA(4))
CL =TVCL*EXP(ETA(1))
TVV =THETA(3)
V =TVV
S2 =V
$ERROR
IPRED = F
W=IPRED+0.000001
IRES=DV-IPRED
IWRES=IRES/W
Y = F*EXP(ERR(1))
SNUH-CTC
Simulation Plan
Actual US Results
Comparison
Korean Study
Dose
AUC
US Study
Dose
AUC
Response
Emax
Model
Response
SNUH-CTC
Trial Simulation Platform
5 dose group (0, 7.5, 15, 30, 45 mg, N=500), 300 replications
SNUH-CTC
25
US 30mg Group
Mean Effect = -1.749
20.5 percentile
20
15
10
Median = -1.975
5
0
-5.0
-4.6
-4.2
-3.8
-3.4
-3.0
-2.6
-2.2
-1.8
-1.4
-1.0
-0.6
-0.2
Distribution of 300 Mean Changes in FBG (mM) of Korean 15mg Group
SNUH-CTC
US actual trial 45mg Group
Mean Effect = -3.0745
53.2 percentile
25
20
15
Median = -3.04
10
5
0
-5.0
-4.6
-4.2
-3.8
-3.4
-3.0
-2.6
-2.2
-1.8
-1.4
-1.0
Distribution of 300 Mean Changes in FBG (mM) of Korean 30 mg Group
SNUH-CTC
Overlapping of Effect Range
Dose For US patients (mg/day)
45
60
30.0
45.0
-5
0
5
30
US
Korean
-10
Change From Baseline
MeanCFBG
Predicted
Predicted
0
0.0
7.5
15.0
Dose For Korean patients (mg/day)
SNUH-CTC





Conclusion
Bridging concept is actively applied but regulatory
experience is still limited in Korea.
No official bridging study has been requested by
Korean regulatory body until now.
Differences in pharmacokinetics among ethnic groups
(even between Japanese and Korean) were
frequently observed.
Mechanisms and clinical implications of such PK
differences should be explored and reflected in local
label on scientific bases.
Need sponsors’ cooperation and changes in attitude
(strategy ?) toward more scientific and informative
clinical development in Korea.