Foreign Clinical Studies

1
Foreign Clinical Studies

• Carol H. Danielson, MS, DrPH
• President
• Regulatory Advantage

2
Globalization of Clinical Research
3
Increase in IND Foreign Investigators (1980-1999)

• 1980 41
• 1990 271
• 1999 4,458
• DHHS, OIG Report
  (FR04130163)

4
Foreign Studies (1995-1999)

• 35 of trials conducted under INDs included
  foreign sites
• 1, 140 foreign studies conducted annually under
  INDs.
• 575 foreign studies conducted annually not under
  INDs.
• CDER Internal Analysis
  (FR04130163)

5
Global Research Since 1990-2000

• Scope of Global research has grown from 28 to 79
  countries.
• Number of Investigators in global research has
  increased 16 fold.
• OIG September 2001

6
Global Research Today

• More than one-fourth of subjects in studies
  conducted by the NIH are in non-U.S. studies.
• Approximately 30 of clinical trials submitted to
  the FDA are conducted outside the USA.
• Applied Clinical
  Trails (2005)

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FDAs Expectationsfor Foreign Clinical Data
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Foreign Data in Marketing Applications

• 1. Multi-site IND Studies
• 2. U.S. Plus Foreign Studies
• 3. Foreign Studies Only

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3 Ways to Use Foreign Data


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Foreign Clinical Studies Under the IND

• Multi-site or stand-alone
• Meets requirements of 21 CFR 312 and other FDA
  regulations
• Conducted according to GCPs

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Foreign Clinical Studies Not Under the IND

• Well-designed
• Well-conducted
• Qualified Investigators
• Ethical Principles Acceptable to World Community
  (GCP/ Declaration of Helsinki)
• 21 CRF
  312.120

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Foreign Studies as Sole Support for NDA

• Applicable to U.S.
• Competent Investigators
• Data can be Validated
• Consultation with FDA
• 21 CFR
  314.106

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Ethnic Factors in Acceptability of Foreign Data

• May be Intrinsic or Extrinsic
• Applicable to U.S. Population
• Applicable to U.S. Practice of Medicine
• Bridging Studies May be Required

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Apply to U.S. Population

• Extrapolate Foreign Data to U.S.
• Racial Distribution
• Demographic Rule
• Drugs Sensitive to Ethnic factors

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Apply to U.S. Medical Practice

• Diagnosis and Patient Management
• Concomitant Medications
• Prior and Concurrent Treatments
• Cultural Differences in Practice

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Ethnic Factors in Drug Response

• Whites Metabolism of anti depressants, anti
  psychotics, and beta blockers
• Blacks Response to antihypertensive agents (beta
  blockers and ACE inhibitors) and interferon-alpha
  
• Dermatological other topicals response differs by
  skin structure and physiology

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Good Clinical Practices

• Informed Consent
• Ethics Review
• Well-designed Protocols
• Data Accuracy
• Data Integrity
• ICH, E.6

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Why Go Ex-US?
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10 Reasons to Go Ex-U.S.

• Rapid Enrollment
• Lower Investigator and Site Costs
• Expanded Patient Population
• Increased Patient compliance
• Treatment-naïve Patient Population

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10 Reasons (Contd)

• Competing Studies in U.S.
• Decreased Regulatory Burden
• Prevalence of Disease or Condition
• Access to Both Hemispheres and Varied Climatic
  Conditions
• Multi-site Global Development Plan

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Speed to Market
22
Clinical Development
IND to NDA
8-10 years
Drug Substance
Drug Product Formulation
Genotox Acute
Repro Chronic Toxicology
Carcinogenicity
Phase 0,1
Phase II
Phase III
Phase IV
23
Costs to Develop a New Drug

• 54 million in 1979
• 231 million in 1987
• 802 million in 2000
• (231 million in 1987318 million in 2000 based
  on inflation)

24
Increasing Speed to Market

• Fastest Development companies in 2000- 2005 saved
  17 months in development and regulatory review
  compared to average companies.
• Fastest companies were Bayer, Astra-Zenaca,
  Allergan, Boehringer Ingelheim, and Merck

25
Increasing Speed to Market

• Between 2000 and 2005 drug companies that were
  fasted to market gained 1.1 billion in
  incremental prescription revenue and saved 30
  million in out-of-pocket costs compared to
  slowest companies.
• September/October Tufts CSDD Impact Report

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Region Specific Advantages and Challenges
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Global Clinical Sites

• Canada and Australia
• Western Europe
• Central and Eastern Europe
• Latin America
• Asia and India
• Africa and the Middle East

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Group 1 Sites

• Canada
• Australia and New Zealand
• Western Europe
• (Japan)
• (South Africa)

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Group 2 Sites

• Latin America
• Central and Eastern Europe
• India

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Group 3 Sites

• Asia (China and SE Asia)
• Africa (N. of S. Africa)
• Middle East
• Other

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Challenges in Emerging and Special Issue Sites

• Logistics (travel, language, mail etc.)
• Regulatory delays
• Need for local agents
• Compliance with GCPs
• Cultural Differences
• Sociopolitical unrest

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Resources

• FDA and ICH
• Guidance
• Documents

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Acceptance of Foreign Data

• Guidance for Industry Acceptance of Foreign
  Clinical Studies, March 2001

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Ethnic Factors

• Guidance for Industry (E5) Ethnic Factors in the
  Acceptability of Foreign Data, June 1999
• QA September, 2006

35
Demographic Rule

• Guidance for Industry Collection of Race and
  Ethnicity Data in Clinical Trails, September 2005

36
Good Clinical Practices

• Guidance for Industry (E6) Good Clinical
  Practice, Consolidated Guidance, April 1996