ADVANCED WORKSHOP : REVIEW OF
DRUG DEVELOPMENT IN CLINICAL
TRIALS
BANGKOK, 2-6 FEB 2009
Review principles of dose selection
Junko Sato
Review Director, Office of New Drug I
Pharmaceuticals and Medical Devices Agency
(PMDA)
Current guideline
Dose-Response information to support Drug
Registration
http://www.ich.org/LOB/media/MEDIA480.pdf
Exposure-Response Relationships — Study
Design, Data Analysis, and Regulatory
Applications
ICH-E4,
1994
FDA, 2003
http://www.fda.gov/cder/guidance/5341fnl.pdf
Point to Consider on Pharmacokinetics and
Pharmacodynamics in the Development of
Antimicrobial Medicinal Products
EMEA,
2000
http://www.emea.europa.eu/pdfs/human/ewp/265599en.pdf
APEC LSIF PROJECT “Capacity
Building For Drug Regulatory Agencies
on Clinical Trial and Good Clinical
Practice (Phase 2)”
1
ADVANCED WORKSHOP : REVIEW OF
DRUG DEVELOPMENT IN CLINICAL
TRIALS
BANGKOK, 2-6 FEB 2009
How to choose dosage ?
-at beginning of Ph2‹
Non-clinical data
Pharmacology
™ Toxicology
™ PK/PD in animal models
™
‹
2 or more dosages
will be chosen for
Ph3 studies
PK in healthy volunteers (PhI)
How often ?
How much ?
How to choose dosage ?
-at beginning of Ph3‹
Result of Ph2
Which dosage is more effective than other dosage?
™ Which dosage is safer than other dosage?
™
Benefit/Risk balance is important !
APEC LSIF PROJECT “Capacity
Building For Drug Regulatory Agencies
on Clinical Trial and Good Clinical
Practice (Phase 2)”
2
ADVANCED WORKSHOP : REVIEW OF
DRUG DEVELOPMENT IN CLINICAL
TRIALS
BANGKOK, 2-6 FEB 2009
How to judge benefit/risk balance ?
Benefit > Risks
‹ All drugs have some side effects.
‹
Can the risk be managed?
™ How to manage the risks?
™
Does the benefit exceed the risk?
‹ Benefit/Risk balance is not judged by absolute
value of ADRs. It is judged relatively.
‹
Example:
These ADRs are reported
in the clinical trial of oral
antimicrobial agents.
Can you approve it ?
Pharyngitis？
Is benefits
larger than
risks ?
Tonsillitis？
APEC LSIF PROJECT “Capacity
Building For Drug Regulatory Agencies
on Clinical Trial and Good Clinical
Practice (Phase 2)”
3
ADVANCED WORKSHOP : REVIEW OF
DRUG DEVELOPMENT IN CLINICAL
TRIALS
BANGKOK, 2-6 FEB 2009
Acceptable risks
Magnitude of acceptable risks depend on
magnitude of benefit
‹ If available benefit are large, magnitude of
acceptable risk will be large.
‹ Manageable ?
‹
Measure to avoid risks
™ Early detection
™
APEC LSIF PROJECT “Capacity
Building For Drug Regulatory Agencies
on Clinical Trial and Good Clinical
Practice (Phase 2)”
4
ADVANCED WORKSHOP : REVIEW OF
DRUG DEVELOPMENT IN CLINICAL
TRIALS
BANGKOK, 2-6 FEB 2009
Example；Rosuvastatin
Rosuvastatin
One of statin class of lipid-lowering
compounds which inhibit HMG-CoA
reductase and reduce cholesterol synthesis.
‹ Class side effect :muscle toxicity (including
rhabdomyolysis) , liver toxicity,
thrombocytopenia
‹
APEC LSIF PROJECT “Capacity
Building For Drug Regulatory Agencies
on Clinical Trial and Good Clinical
Practice (Phase 2)”
5
ADVANCED WORKSHOP : REVIEW OF
DRUG DEVELOPMENT IN CLINICAL
TRIALS
BANGKOK, 2-6 FEB 2009
Efficacy
Rosuvastatin : D/R relationship
D/R : Dose/Response
APEC LSIF PROJECT “Capacity
Building For Drug Regulatory Agencies
on Clinical Trial and Good Clinical
Practice (Phase 2)”
6
ADVANCED WORKSHOP : REVIEW OF
DRUG DEVELOPMENT IN CLINICAL
TRIALS
BANGKOK, 2-6 FEB 2009
Compare efficacy with other statins
Percent Change in LDL-C From Baseline to Week 6 (LS Mean*)
(sample sizes ranging from 156–167 patients per group)
Safety
- ADRs in each dosage -
(% of Patients)
APEC LSIF PROJECT “Capacity
Building For Drug Regulatory Agencies
on Clinical Trial and Good Clinical
Practice (Phase 2)”
7
ADVANCED WORKSHOP : REVIEW OF
DRUG DEVELOPMENT IN CLINICAL
TRIALS
BANGKOK, 2-6 FEB 2009
Class side effects
Liver toxicity
APEC LSIF PROJECT “Capacity
Building For Drug Regulatory Agencies
on Clinical Trial and Good Clinical
Practice (Phase 2)”
8
ADVANCED WORKSHOP : REVIEW OF
DRUG DEVELOPMENT IN CLINICAL
TRIALS
BANGKOK, 2-6 FEB 2009
Class side effects
Muscle toxicity
APEC LSIF PROJECT “Capacity
Building For Drug Regulatory Agencies
on Clinical Trial and Good Clinical
Practice (Phase 2)”
9
ADVANCED WORKSHOP : REVIEW OF
DRUG DEVELOPMENT IN CLINICAL
TRIALS
APEC LSIF PROJECT “Capacity
Building For Drug Regulatory Agencies
on Clinical Trial and Good Clinical
Practice (Phase 2)”
BANGKOK, 2-6 FEB 2009
10
ADVANCED WORKSHOP : REVIEW OF
DRUG DEVELOPMENT IN CLINICAL
TRIALS
BANGKOK, 2-6 FEB 2009
Which dose do you choose?
Why ?
Dosage in US Labeling
APEC LSIF PROJECT “Capacity
Building For Drug Regulatory Agencies
on Clinical Trial and Good Clinical
Practice (Phase 2)”
11
ADVANCED WORKSHOP : REVIEW OF
DRUG DEVELOPMENT IN CLINICAL
TRIALS
BANGKOK, 2-6 FEB 2009
Review of rosuvastatin in Japan
Rosuvastatin was approved in US with 5-40mg
in US before approval in Japan.
‹ ‘Bridging’ strategy was used for development
in Japan.
‹
Clinical Data Package in Bridging Strategy
US or EU
Japan
PK/PD study
①
PK/PD study
Bridging study
②
Bridging
corresponding study
Therapeutic Confirmatory
③
APEC LSIF PROJECT “Capacity
Building For Drug Regulatory Agencies
on Clinical Trial and Good Clinical
Practice (Phase 2)”
Long-term administration
Special population
12
ADVANCED WORKSHOP : REVIEW OF
DRUG DEVELOPMENT IN CLINICAL
TRIALS
BANGKOK, 2-6 FEB 2009
Ethnic difference in LDL Level
‹
Serum cholesterol level in US subjects is
higher than Japanese subjects.
Dose the difference influence efficacy ?
‹
Prevalence of coronary heart disease in the
Japanese is 1/4 of foreigners.
How to consider these differences ?
From Review report in Japan
Serum cholesterol level & prevalence of
coronary heart disease are different between
Japanese and foreigners.
‹ There are no difference below;
‹
Relationship between total cholesterol &
prevalence of CHD
™ Relationship between total cholesterol & mortality
™
APEC LSIF PROJECT “Capacity
Building For Drug Regulatory Agencies
on Clinical Trial and Good Clinical
Practice (Phase 2)”
13
ADVANCED WORKSHOP : REVIEW OF
DRUG DEVELOPMENT IN CLINICAL
TRIALS
BANGKOK, 2-6 FEB 2009
Same t-chol brings same prevalence
Prevalence of CHD
Japanese
American
There are no ethnic difference
between serum cholesterol level and risk of CHD.
Total cholesterol
Ethnic Difference in PK
APEC LSIF PROJECT “Capacity
Building For Drug Regulatory Agencies
on Clinical Trial and Good Clinical
Practice (Phase 2)”
14
ADVANCED WORKSHOP : REVIEW OF
DRUG DEVELOPMENT IN CLINICAL
TRIALS
BANGKOK, 2-6 FEB 2009
American
Japanese
How about E/R ?
N
No. of ADR(Pts.)
%
No. of ADR(events)
General
disorder
Cardio
GI
Hepato
-bilialy
blood
metabo
muscle
neuro
special
sence
}
Urinary
disorder
APEC LSIF PROJECT “Capacity
Building For Drug Regulatory Agencies
on Clinical Trial and Good Clinical
Practice (Phase 2)”
15
ADVANCED WORKSHOP : REVIEW OF
DRUG DEVELOPMENT IN CLINICAL
TRIALS
BANGKOK, 2-6 FEB 2009
How to choose the dosage?
5-10mg of the drug is superior to 10mg of
atrvastatin, 20mg of pravastatin and simvastatin.
‹ 80mg wasn’t approved in US by occasion for
safety, cf. myopathy.
‹ The range of efficacy overlapped for 20 mg and
40mg in Japanese, as well as 40mg and 80mg in
American.
‹ 10mg and 20mg in Japanese weren’t overlapped,
but risk is a little higher than lower dosage.
‹
Approved dosage in Japan
Starting dose : 2.5mg QD
‹ If sufficient efficacy is not available after 4
weeks from starting or increasing dose, dose
can be increased by 10mg, eventually.
‹ If reduction of LDL is insufficient by 10mg
administration, dose can be increased by 20mg.
20mg is restricted to use for severe subjects.
‹
APEC LSIF PROJECT “Capacity
Building For Drug Regulatory Agencies
on Clinical Trial and Good Clinical
Practice (Phase 2)”
16
ADVANCED WORKSHOP : REVIEW OF
DRUG DEVELOPMENT IN CLINICAL
TRIALS
BANGKOK, 2-6 FEB 2009
Benefit/Risk Balance is Key !
‹
‹
‹
If the effect rises along with increasing the dosage,
we would like to select higher dosage.
But, if risk also increase with dose up, we cannot
select higher dosage.
On risk evaluation,
™
™
™
™
Frequency of ADRs
Severity of ADRs
Tolerability in physically and philosophically
Manageable or not
‹
‹
To avoid
For early detection
APEC LSIF PROJECT “Capacity
Building For Drug Regulatory Agencies
on Clinical Trial and Good Clinical
Practice (Phase 2)”
17