global drug development to bridge or not to bridge

Global Drug Development

To Bridge or Not to Bridge

Points to Consider in Bridging

• Specific Country Requirements

• What is the “Societal” value of the product?

• What are the cultural differences that may influence the acceptance of “bridging?”

• It is possible?

Points to Consider in Drug Development

Product Company IndicationNumber of Subjects in

Date of Approval

Sildenafil (Viagra) Pfizer Erectile Dysfunction 289 Jan-99Donepezil (Aricept) Eisai Alzheimer's Disease 705 Oct-99

Fexofenadine (Allegra) Aventis PharmaAllergic Rhinitis/Urticaria 841 Sep-00

Anastrozole (Arimidex) Astra Zeneca Breast Cancer 124 Dec-00Oseltamivir‡ (Tamiflu) Roche Influenza 624 Dec-00Alendronate (Fosamac)† Merck/Teijin Osteoporosis 1157 Jun-01Zolmitriptan (Zomig) Astra Zeneca Migraine 289 Jun-01Sumatriptan (Imigran) GlaxoSmithKline Migraine 230 Jun-01Insulin aspart (NovoRapid) Novo Nordisk Diabetes mellitus 240 Oct-01

Imatinib (Glivec) NovartisChronic myelogenous leukemia 66 Nov-01

Palivizumab (Synagis) Abbott RSV Infection 31 Jan-02Risedronate (Actonel)§ Ajinomoto/Takeda Osteoporosis 761 Jan-02Goserelin (Zoladex) Astra Zeneca Prostate Cancer 40 Jan-02Basiliximab (Simulect) Novartis Renal transplant 31 Jan-02Infliximab (Remicade) Tanabe Crohn's Disease 27 Jan-02Eletriptan (Relpax) Pfizer Migraine 321 Apr-02Omeprazole/Amoxicillin/ Clarithromycin (Omepral et al) Astra Zeneca H.pylori infection 563 Apr-02Exemestane (Aromasin) Pharmacia Breast Cancer 107 Jul-02

Gefitinib (Iressa) Astra ZenecaNon-small cell lung cancer 133 Jul-02

Brinzolamide (Azopt) Alcon Glaucoma 70 Oct-02Leflunomide (Arava) Aventis Pharma Rheumatoid arthritis 366 Apr-03

Bridging is Now “Old”

• ICH E5 reached Step 4 on February 5, 1998– More than 8 years ago!

• What was it really?– A excellence guide to drug development

irrespective of ethnicity

• What is really next?

Global Development of Medications for Type 2 Diabetes

• Type 2 Diabetes as a global disease• The ethnicity of type 2 diabetes

– Controversy-cell dysfunction• Insulin resistance• “BMI confusion”

• “Bridging” & “Global development”• Ethnicity and the concerns of Regulatory

Authorities

Type 2 diabetes as a global disease

Number of T2DM

135

300

5172 84

228

0

50

100

150

200

250

300

350

1995 2025 1995 2025 1995 2025

Mill

ion

s

Total

Developed

Developing

Type 2 diabetes as a global disease

T2DM - Heterogeneous Disease

• The concept of heterogeneity

– Has a long history

• Phenomenological (Empiric)– Type 1 (Juvenile diabetes, IDDM, etc.)

» Generally autoimmune

– Type 2 (Adult diabetes mellitus, NIDDM, etc.)

-cell dysfunction

» insulin-resistance)

– MODY

T2DM - Heterogeneous Disease

• The concept of heterogeneity (Type 2)– MODY as a model

• Glucokinase• HNFs• Other...

– Differences in body size.• High BMI versus Lower BMI• Impaired -cell (“little pancreas”) versus Insulin

resistance (“big pancreas”)

– Observed differences in insulin secretion

T2DM - Ethnically Heterogeneous Disease

0.0

1.2

1.6

2.7

4.0

4.3

6.1

8.6

6.1

10.5

13.1

14.1

14.2

22.0

41.3

50.3

0 20 40 60 80 100

Melanesia

Bantu

Chinese (China)

Asian India (rural)

Polynesian (rural)

Micronesia (rural)

White (US)

Melanesia (urban)

Black (US)

Polynesian (urban)

Chinese (Mauritius)

Mexican American

Arab

Asian Indian (Fiji)

Micronesia (Nauru)

Native American (Pima)


• Popular view of diabetes in Asia

• Popular view of diabetes in the West

Need for Special “Asian” studies

Western studiesnot relevant to Asia

Consequences of “Difference”

• Full (extensive) development in each Region– Pathogenic differences

– Different cultures• Foods

• Medical Practice

– Different perceptions of risk & benefit• “Looks different, therefore, risk assessment is

different”

Foundation of Type 2 Diabetes

• Undoubtedly with genetic roots– > 90% of monozygotic twins are concordant 38% of siblings are concordant

• Known genetic polymorphisms - MODY– Found in all ethnic groups (Caucasian, Japanese,

Chinese, etc…)– Account for a small percentage of diabetes

• None of the candidate genes explain a significant percentage of cases

• “The geneticists’ nightmare”


• Undoubtedly with genetic roots– “Biomarkers” must exist– Comparisons among populations (and individuals) are justified

• Comparisons are, however, confounded– Multiple sources of bias

• Sampling differences– Differences in duration of disease– Differences in awareness of disease– Differences in medical practice

• Differences of assay methods• Temporal differences (varying degrees of affluence)

– Differences of interpretation of results


• Common themes and controversies -cell dysfunction

– “Insulin resistance”

+++ -cell+ “Insulin resistance”

+ -cell+++ “Insulin resistance”


• Controversial but basic agreement

– Combination of

-cell dysfunction

• Insulin resistance


• Evidence for similarities among ethnic

groups• Impairment in insulin secretion is observed in

many ethnic groups.

– Japanese

– Caucasians

– Mexican Americans

– African Americans



groups• Evidence of insulin resistance

– Japanese

– Caucasians

– Mexican Americans

– African Americans



groups• Similar behavior of associated biomarkers

– Reduced adiponectin associated with T2DM

» Japanese

» Caucasians

» Chinese

» African Americans



groups• Similar behavior of associated biomarkers

– Increased C-reactive protein associated with T2DM

» Japanese

» Caucasians

» Chinese

» African Americans

» Mexican Americans


• Actual situation of T2DM in Asia

• Actual situation of T2DM in the West


• “Bridging” or global drug development

– ICH E5 guideline (considerations for

development in different ethnic groups

• FDA has issued guideline for

development in various ethnic groups


• “Bridging” has been applied primarily to

the registration of various medications

in the Japan and some other Asian

markets.

• By and large it has been successful


• Thus far only one development for T2DM has

been bridged

– NovoRapid

• However, it should not be concluded:

– Bridging is not possible

– Japan and other Asian nations cannot contribute to

global drug development


• ICH GCP has been adopted– US

– EU (Western & Central Europe)

– Japan

– Many Asian nations (Korea, Taiwan, etc.)

• Infrastructure improving– Asia

– Central Europe


• Logistics of a Global Development

– A global development program• Protocols

• Endpoints

• Assays

• Analytical methods



– Endpoints (Good news)

• HbA1c widely accepted

– HbA1c is standardized for the measurement

of “stable” HbA1c

• Not so good news

– Slight differences persist between Regions



– Endpoints (Area of potential controversy)

• Insulin assays are NOT standardized

• C-reactive protein assays are NOT

standardized

• Adiponectin assays are NOT standardized



– Insulin Assay (example)

• Same population

– US

– Demographics (Age, Sex distribution, BMI)

• Very different baseline IRI



– Insulin Assay (Consequences)

• Interpretation of HOMA-IR

– (F-IRI (U/mL) X FPG (mmol/L))/22.5

Recommendations to Consider in Drug Development

• Global KOL panel (US, EU & Asia)

• Many prominent Japanese & Korean KOLs have trained

extensively in US or Europe

• Global Protocol

– Primary Endpoint Identical across regions

• Global Core Laboratory

– HbA1c, Insulin, other biomarkers


• Global approach to Regulatory Authorities

– US

– EU

– Japan

– Asia Pacific (China, Taiwan, Korea)


• Requires engagement with Investigators

from different regions

• Requires modifications within the R&D

organization

global drug development to bridge or not to bridge

Documents

diabetes type

different slide

asia slide

global disease slide

insulin secretion slide

heterogeneous disease

drug development slide

foundation of type