Download Global Development Paradigm 2 - Drug Information Association

Asian Ethnicity & Drug
Development-Regulatory Risk
Ethnic Differences and Global Drug Development
Drug Information Association
Beijing, China
May 18,2011
Bob Powell
Clinical Pharmacology
Roche Beijing
[email protected]
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If there are true ethnic differences we should:
• Decide if ethnic differences (e.g., disease
biology) are likely to be clinically significant
– When unclear, possibly do further research to
clarify significance
• Account for clinically significant differences in
big decisions (e.g., development strategy, trial
design, approval, labeling)
Do we do either in a systematic manner?
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Preventing Lethal Drug Effect in Chinese Patients
A Case Study
• Carbamazepine (CBZ): most common cause of Steven-Johnson
Syndrome (SJS) & Toxic Epidermal Necrolysis (TEN) in SE Asia
• Mortality SJS (5%) & TEN (25-35%). Fever, malaise, skin lesions
like a bad burn…skin detaches.
• Genetic test (HLA-B*1505 allele) predictive in Han Chinese
(98.3% sensitivity, 95.8% specificity)
• Prospective study: 4877 Taiwanese patients prospectively
tested for HLA-B*1505 allele, 7.7% positive-advised to avoid
CBZ
• SJS-TEN did not develop in any negative patient taking CBZ
Should Ethnicity be accounted for in treating Chinese patients
with CBZ?
NEJM 364: 1126-1133 , 2011
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• Should ethnicity be accounted for when prospectively
developing new drugs?
• Potential consequences of not accounting for ethnicity in
new drug development:
• Drug companies
–
–
–
–
Efficacy & Safety: uncontrolled. Trial design. Trial failure
Dosing. Same for all.
Clinical trials:  failure rate  delayed approval   revenue
Labeling. Local directions may not provide accurate information
guiding use
–  market if product not well tolerated
• Regulators (CDE)
– Ambiguous trial results making approval decision more difficult
– Inaccurate estimates of true efficacy &/or toxicity
– Potential post-market problems if significant toxicity issues occur….if
they can be detected
• Patients-Physicians
– Drug does not perform as advertised. Market may decrease
4
Can Diseases in China-Asia be Different?
• Chinese-Asian known disease differences
– Prevalence
• GI cancers ↑ (stomach, liver, bowel)
• Hepatitis
• Self inflicted injuries
– Disease biology
• NSCLC-EGFR+ 3-4x
• Hepatitis B &C genotypes
– Phenotype
• Type 2 diabetes-Children – obese ↑+ Adults normal weight → ↑Risk
• Breast cancer- menopausal Pre > Post
– Criteria for diagnosis & assessment
• Depression & other diseases described by symptoms-behaviors
5
Can Therapeutics in China-Asia be Different?
• Therapeutic response
– Better Asian response
• Non small cell lung cancer- 3-4X ↑ EGFR+
• Hepatitis C-size
– Worse Asian response
• Hepatitis B-viral genotype
• Breast cancer response to tamoxifen-(↓active
metabolite)
• Drug toxicity
– Chemotherapy
– Interferon (HBC)
– Carbamazepine
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Are Chinese-Asians Different Regarding:
• Dosing
– Increased effect due to either ↑ exposure
(↓clearance) or ↑ dynamic effect: ethanol,
prasugrel, heparin, propranolol, ….
• Physiology: Differences in size, gastric acidity,
metabolism, transporters
• Variability (weight as biomarker)
• Chinese > Japanese
• Disease stage at diagnosis
• Baseline treatment
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Are People Different?
(mean weight (kg))
USA1
2002
China 20022
(45-59 years)
(50-59
years)
Big City
(>500k)
Town
(200-500k)
Rural 1
(richer)
Rural 2
Rural 3
Rural 4
(poorest)
Males
88.8
68.9
66.6
63.0
60.5
63.6
57.9
Females
76.9
61.1
59.4
57.5
54.8
58.1
52.3
• Clcr (ml/min) estimated for 59 yo, 88.8 kg American ♂versus 52.3 kg Chinese ♀ is 99.9
ml/min versus 50.0 ml/min.
• Might weight difference (amount, composition) lead to pharmacologic differences?
• Size differences not accounted for in clinical trial planning-rather post hoc analysis
1.
2.
CDC US mean body weight, height, bmi 1960-2002 http://www.cdc.gov/nchs/data/ad/ad347.pdf
A Survey on Nutrition and Health in Chinese Citizens. Wang Longde
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Historically
• Assumed ethnic differences limited to drug metabolism as
reflected in pharmacokinetics
• ICH5 ‘ETHNIC FACTORS IN THE ACCEPTABILITY OF FOREIGN CLINICAL
DATA’ (http://www.ich.org/LOB/media/MEDIA481.pdf) 1997
– Premise.
• Development efficiency- sharing development data for regulatory
decisions between regions
• ‘Acceptability of the foreign clinical data component of the complete data
package depends then upon whether it can be extrapolated to the
population of the new region.’
– Focus. Pharmacokinetics, pharmacodynamics, dose-response, efficacy,
safety, clinical trial standards.
– Disease topics….limited discussion
• Endpoints for assessing treatment effectiveness
• Medical and diagnostic definitions acceptable to the new region
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Japanese Approved (2001-7, N=137) Drug Dose
Ratios (US/Japan)
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Clin Pharm Ther 87:714, 2010
Current Development-Regulatory Scenarios
1. Sequential: approve elsewhere, local bridge  2-5 year market lag
Dose-Response
Phase 3 Confirm
Reviews
Bridging
SFDA
China
Japan
FDA
U.S.-EU
Review
EMEA
PMDA
Approvals
Approvals
•
•
China
PK study in China
Modified Phase 3 trial
100 patients each
new drug + comparator
2. Parallel: Global development plan & Phase 3 trial(s), simultaneous approvals
Dose-Response
U.S.-EU
Asia
(pk or dose-response)
Phase 3 Confirm
Reviews
U.S.-EU
Asia
FDA
(multi-regional clinical trial)
SFDA
EMEA
•
•
Japan
Dose-response
Efficacy-safety
1997 Global clinical trial
PMDA
Which scenario meets local patient needs ?
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Global Development Paradigm 1 (sequential)
Bridging
(lag time 2-5 years in bridged countries)
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Global Development Paradigm 2 (parallel)
(Global Clinical Trials-Japanese Recommendation)
What if major ethnic differences exist in disease or pharmacology?
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Global Development Paradigm 3
(Bi-Regional Multicenter Clinical Trials)
• Might this be more informative and lower risk than Global trials?
• Or…. designing trials based on patient comparability
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The Troll Under the Bridge is Named…..
US-EU
NDA
NDA
• Ethnicity
• Local practices
ASIA
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Country-Region Knowledge Needed to Support Drug R&D
(links to genetics & ethnicity)
Value
Pharmacology (ADME PK-PD)
• Body effect on drug & drug effect on body
Epidemiology
• Disease in whom, outcomes & relationships?
Disease Biology
• Disease mechanism(s)
Population Demographics
• Who lives there?
Valuable prior knowledge   development risk
16
Governments Need to Support Information Development & Sharing
(supporting drug & device development)
Information Gap Needs to be Filled
Local Government Primary Responsibility
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New Chemical Entity (NCE)
Global Development Planning
Ethnic-Regional Analysis
Quantitative-Qualitative
NCE
+
Target Product
Profile
• Demographics
• Disease pathophysiology
& epidemiology
• Pharmacology
• Pharmacokinetics
• Pharmacodynamics
• Medical practice
Ethnic-Regional
Patients the Same
?
Yes
No
DevelopmentRegulatory
Strategy
Dosing
Trial
Design
Same
Global
Different
Regional
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New Chemical Entity (NCE)
Global Development Planning
Ethnic-Regional Analysis
Quantitative-Qualitative
NCE
+
Target Product
Profile
• Demographics
• Disease pathophysiology
& epidemiology
• Pharmacology
• Pharmacokinetics
• Pharmacodynamics
• Medical practice
Ethnic-Regional
Patients the Same
?
Yes
No
DevelopmentRegulatory
Strategy
Dosing
Trial
Design
Same
Global
Different
Regional
Phase 3 Global Clinical Trial Planning
• Uniform inclusion-exclusion
criteria
• Same dose for all
• Does not include ethnicity curiosity
(disease, drug, patient size, local
practice) on trial outcome
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New Chemical Entity (NCE)
Global Development Planning
Ethnic-Regional Analysis
Quantitative-Qualitative
NCE
+
Target Product
Profile
• Demographics
• Disease pathophysiology
& epidemiology
• Pharmacology
• Pharmacokinetics
• Pharmacodynamics
• Medical practice
Ethnic-Regional
Patients the Same
?
Yes
No
DevelopmentRegulatory
Strategy
Dosing
Trial
Design
Same
Global
Different
Regional
Decide
Prior Knowledge
Simulate
scenarios
Disease-drug
modeling
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1. Simulate Chinese Pharmacokinetics from Prior Known Chinese
Physiology (e.g., Simcyp, GastroPlus, Matlab)
Drug Characteristics
Physiologic PK Modeling
• Physico-chemical (pKa, clogP,
MW, solubility)
• Tissue binding (plasma, blood,
tissues)
• Clearance
• Fractional (renal, hepatic)
• Hepatic microsomes
(Vmax, Km)
Chinese
• Renal failure
• Adults
• Children • Hepatic failure
• Elderly
2. Decide Dose-Response Information Needed in Chinese Patients
Options (simulated design)
Phase III Confirmation
•
•
•
•
(simulated design, population PK-PD)
PK only
Single dose PK-PD
Multiple dose PK-PD
Dose-ranging in patients
(PK-PD)
• Global multi-center clinical trial
• Regional MRCT
• Local (China) MRCT
Submit NDA
3. Postmarket confimation in special populations (pediatrics,
elderly, organ failure)
a) Decide which special populations are important to confirm
in Chinese patients
b) Decide if confirmation needed using PK only, PK-PD, or an
efficacy-safety trial
c) Simulate trial based on prior knowledge with this drug and
others + earlier PBPK simulations
d) Consider Bayesian trial design to be more efficient with
patient numbers.
Summary
• Size, disease & pharmacology can lead to significant differences in
efficacy, safety & dose requirements between global regions
• Should ICH E5 be revised or ammended?
• ‘Bridging’ is becoming bi-directional (west to east, east to west)
• Recognizing patient potential differences requires greater curiosity
& flexibility in drug development
• Asian governments need to better define patient ethnicity
similarities-differences making information publically available
• Companies and regulators need to invest in ethnicity prediction….
initial basis for ethnicity importance
• Greater regulatory ethnicity emphasis & clarity is needed.
• Is there a need for a yearly science conference?
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Ethnicity Significance in Drug Research & Development)
(Disease, Dosing, Efficacy & Safety)
a proposed yearly conference
• Objectives
– To review ethnicity science for disease (biology, demographics, morbidity,
mortality) and pharmacology-therapeutics (dose-response, efficacy, safety)
– To describe local differences in medical practice likely to influence clinical trial
outcome
– To consider the impact of global development scenarios when drugs are
developed in one region and seek registration in others.
– To evaluation ethnicity prediction based on laboratory tests and in silico
models
– To identify significant information gaps requiring research
• Format
– 2 day yearly international conference held in China
• Participants
– Physicians, biostatisticians, clinical pharmacologists, epidemiologists
– Academia, pharmaceutical industry, regulatory agencies
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