Global Drug Development

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Global Drug Development

• To Bridge or Not to Bridge

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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?

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Points to Consider in Drug Development
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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?

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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

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Type 2 diabetes as a global disease
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Type 2 diabetes as a global disease
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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

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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

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T2DM - Ethnically Heterogeneous Disease
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T2DM - Ethnically Heterogeneous Disease
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T2DM - Ethnically Heterogeneous Disease
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T2DM - Ethnically Heterogeneous Disease
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T2DM - Ethnically Heterogeneous Disease

• Popular view of diabetes in Asia

• Popular view of diabetes in the West

Need for Special Asian studies
Western studies not relevant to Asia
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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

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Foundation of Type 2 Diabetes

• Undoubtedly with genetic roots
• gt 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

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Foundation of Type 2 Diabetes

• 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

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Foundation of Type 2 Diabetes

• Common themes and controversies
• ?-cell dysfunction
• Insulin resistance

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?-cell Insulin resistance
?-cell Insulin resistance
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Foundation of Type 2 Diabetes

• Controversial but basic agreement
• Combination of
• ?-cell dysfunction
• Insulin resistance

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Foundation of Type 2 Diabetes

• Evidence for similarities among ethnic groups
• Impairment in insulin secretion is observed in
  many ethnic groups.
• Japanese
• Caucasians
• Mexican Americans
• African Americans

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Foundation of Type 2 Diabetes

• Evidence for similarities among ethnic groups
• Evidence of insulin resistance
• Japanese
• Caucasians
• Mexican Americans
• African Americans

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Foundation of Type 2 Diabetes

• Evidence for similarities among ethnic groups
• Similar behavior of associated biomarkers
• Reduced adiponectin associated with T2DM
• Japanese
• Caucasians
• Chinese
• African Americans

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Foundation of Type 2 Diabetes

• Evidence for similarities among ethnic groups
• Similar behavior of associated biomarkers
• Increased C-reactive protein associated with T2DM
• Japanese
• Caucasians
• Chinese
• African Americans
• Mexican Americans

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Foundation of Type 2 Diabetes

• Actual situation of T2DM in Asia

• Actual situation of T2DM in the West

?
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Points to Consider in Drug Development

• 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

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Points to Consider in Drug Development

• 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

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Points to Consider in Drug Development

• 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

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Points to Consider in Drug Development

• ICH GCP has been adopted
• US
• EU (Western Central Europe)
• Japan
• Many Asian nations (Korea, Taiwan, etc.)
• Infrastructure improving
• Asia
• Central Europe

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Points to Consider in Drug Development

• Logistics of a Global Development
• A global development program
• Protocols
• Endpoints
• Assays
• Analytical methods

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Points to Consider in Drug Development

• Logistics of a Global Development
• Endpoints (Good news)
• HbA1c widely accepted
• HbA1c is standardized for the measurement of
  stable HbA1c
• Not so good news
• Slight differences persist between Regions

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Points to Consider in Drug Development

• Logistics of a Global Development
• Endpoints (Area of potential controversy)
• Insulin assays are NOT standardized
• C-reactive protein assays are NOT standardized
• Adiponectin assays are NOT standardized

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Points to Consider in Drug Development

• Logistics of a Global Development
• Insulin Assay (example)
• Same population
• US
• Demographics (Age, Sex distribution, BMI)
• Very different baseline IRI

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Points to Consider in Drug Development

• Logistics of a Global Development
• Insulin Assay (Consequences)
• Interpretation of HOMA-IR
• (F-IRI (?U/mL) X FPG (mmol/L))/22.5

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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

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Recommendations to Consider in Drug Development

• Global approach to Regulatory Authorities
• US
• EU
• Japan
• Asia Pacific (China, Taiwan, Korea)

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Recommendations to Consider in Drug Development

• Requires engagement with Investigators from
  different regions
• Requires modifications within the RD organization

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