Quality of Imported Drugs

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Quality of Imported Drugs

• Paul J. Seligman, M.D., M.P.H.
• Associate Director, Safety Policy Communication
• U.S. Food and Drug Administration
• Royal Danish Embassy Conference
• Copenhagen November 5, 2008

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Objectives

• Discuss challenges that globalization presents
  for assuring drug safety
• Discuss activities to address these challenges
• Discuss how FDA integrates with a other
  governmental activities to assure the safety and
  security of imported products

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FDA and Globalization

• One factor demanding our transformation into a
  more expansive agency is the surging
  globalization process that, among many other
  changes, has all but eliminated trade barriers
  along the U.S. borders. Globalization is flooding
  our markets with a myriad of imported goods that
  our consumers want and need, and we are
  responsible for regulating a vast amount of them.
  This means that we have to recreate the FDA.
  After 100 years of operating as a
  quintessentially domestic agency, we must expand
  FDAs reach abroad, and make it a global agency.
  Our modernization is designed to keep substandard
  products off the U.S. market through prevention,
  intervention as well as response. And recognizing
  that inspections at the borders are not an
  impermeable barrier to defective products, we
  must change to oversight of the entire life cycle
  of products -- even as those products grow
  increasingly complex.
• Andrew von Eschenbach, MD
• Commissioner, U.S. Food and Drug
  Administration
• April 25, 2008

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Traditional Import Approach
Ports of Entry
Regulatory Import Decision
Customs Broker
Various Distribution Centers
Foreign Shippers
Importer
Limited Snapshot of Information available to
Regulators Decision Making
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Full Import Life Cycle
U.S Ports of Entry
Foreign Activities
Domestic Activities
Raw Materials
Foreign Mfrs
Foreign Distribution
Foreign Carriers
Domestic Mfrs
Domestic Distributors
Retailers
Consumers End Users
Regulatory Import Decision
Information Flow
Additional Monitoring Points
Additional Monitoring Points
Prevention and Verification Risk-Based
Decision-Making Process
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Traditional Challenges for Assuring Drug Product
Integrity

• Counterfeiting
• Tampering
• Adulteration
• Diversion
• Falsification of original manufacturers

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Globalization

• Imported Drug Shipments
• 2000
• Approx. 1,300 line entries
• 2006
• Over 145,000 line entries
• lt 100x increase over 6 years

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GlobalizationChina and India alone
Listed Number of Drug Manufacturers
Different Types of Imported Drug Items
China 7x increase India 25x increase
China 4x increase India 7x increase
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Globalization

• More sources
• More participants
• More challenges in tracking the whole
  manufacturing and distribution process
• More direct consumer access to prescription
  drugs through the internet and mail

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• Why the concern?

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Elixir of Sulfanilamide

• Sulfa drugs introduced in 1935
• One company uses diethylene glycol to flavor and
  serve as a solvent
• 107 deaths, many of them children
• Led to 1938 FDC Act

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Diethylene Glycol

• Additional outbreaks from medications
  contaminated with DEG
• Bangladesh 1990 over 300 children with kidney
  failure
• Haiti 1996 85 deaths in children
• India 1998 33 deaths in children
• Panama 2006 100s ill and over 40 deaths

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DEG
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Heparin
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Heparin

• Contaminated with overly-sulfated chondroitin
  sulfate
• Not a naturally occurring molecule in levels
  detected
• Similar effect to heparin for blood thinning
• Previously studied as a potential alternative to
  heparin
• Over 60 deaths associated with use of
  contaminated heparin in U.S.
• Additional reports of adverse events related to
  contaminated heparin in Germany and Japan
• Subsequently identified in 11 countries

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Internet Pharmacies and Sales
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Internet Pharmacies and Sales

• Estimates of over 2 million websites selling
  pharmaceuticals
• Unknown sites
• Unknown location
• Unknown credentials
• Unknown products
• Exaggerated claims
• Often cheaper, similar looking
• Internet creates access to U.S. market for
  international companies

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Counterfeits

• Estimated at about 1 in developed countries ..
  but more than 10 in developing countries.

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Counterfeits
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Traditional FDA approach to assure Drug Product
Integrity of Imports - Inspections

• Inspections of imports
• Inspections of manufacturers/suppliers/
  labelers/repackagers/wholesalers

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Why the Traditional Approach is Overrun by
Globalization

• Lack of good information on overseas drug
  manufacturers/suppliers/distributors
• Limited number of FDA inspections overseas
• Lack of authority (international and internet)

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Databases/Information on Imports and Foreign
Manufacturers

• Limited information on drug manufacturers,
  suppliers, etc.
• Siloed information systems - OASIS, FACTS, DRLS
  and CBP
• Unreliable information from foreign sources

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GAO Report

• Drug Safety Preliminary Findings Suggesting
  Weakness in FDAs Program for Inspecting Foreign
  Drug Manufacturers
• Testimony before the Subcommittee on Oversight
  and Investigations, Committee on Energy and
  Commerce, House of Representatives
• November 2007

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GAO Reports

• Weak Databases (inaccurate data)
• Few Inspections (about 200/yr since 2000)
• Unique challenges with overseas inspections
• no dedicated cadre of inspectors
• not unannounced
• limited time and flexibility
• lost in translation
• no regular requirement for foreign inspections
  compared to domestic manufacturers (every 2 yrs)

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Domestic vs. Foreign Inspections
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Flat Funding
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FDA Foreign Inspections
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Inspections

• Unrealistic to inspect every foreign facility
  even if identified
• Unlikely to have authority to perform unannounced
  and complete inspections
• Implications on foreign trade and agreements when
  adverse findings are identified

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• Comprehensive Federal Approach
• To
• Import Safety

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National Strategy on Import Safety

• Interagency Working Group on Import Safety
• Executive Order 13439, July 18, 2007
• Protecting Consumers Every Step of the Way A
  Strategic Framework for Continual Improvement in
  Import Safety, Sept 10, 2007
• Action Plan for Import Safety A roadmap for
  continual improvement, Nov 1, 2007
• 50 action steps in 14 broad recommendations

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Challenges with Current Import System

• Need for comprehensive consideration of risk
• Recognize overlap of the security and safety
  relationship
• Need for additional authorities
• Insufficient data
• Siloed systems
• Circumvention
• Protecting American Consumers Every Step of the
  Way a Strategic Framework for Continual
  Improvement in Import Safety. A Report to the
  President, Interagency Working Group on Import
  Safety, September 2007.

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Import SafetyStrategic Framework

• Prevention
• Intervention
• Response

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Import SafetyAction Plan Building Blocks

• Advance a Common Vision
• Increase Accountability, Enforcement and
  Deterrence
• Focus on Risks Over the Life Cycle of an Imported
  Product
• Build Interoperable Systems
• Foster a Culture of Collaboration
• Promote Technological Innovation and New Science

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Recommendations of the Action Plan for Import
Safety

• 1. Safety Standards Create new and strengthen
  existing safety standards.
• 2. Certification Verify compliance of foreign
  producers with U.S. safety and security standards
  through certification.
• 3. Good Importer Practices Promote Good Importer
  Practices.
• 4. Penalties Strengthen penalties and take
  strong enforcement actions to ensure
  accountability.

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Recommendations of the Action Plan for Import
Safety (cont)

• 5. Foreign Collaboration and Capacity Building
  Make product safety an important principle of our
  diplomatic relationships with foreign countries
  and increase the profile of relevant foreign
  assistance activities.
• 6. Common Mission Harmonize federal government
  procedures and requirements for processing import
  shipments.
• 7. Interoperability Complete a single-window
  interface for the intra-agency, interagency and
  private-sector exchange of import data.
• 8. Information Gathering Create an interactive
  import-safety information network.

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Recommendations of the Action Plan for Import
Safety (cont)

• New Science Expand laboratory capacity and
  develop rapid test methods for swift
  identification of hazards.
• 10. Intellectual Property Protection Strengthen
  protection of intellectual property rights
  (IPR) to enhance consumer safety.
• 11. Recall Maximize the effectiveness of product
  recalls.
• 12. Federal-State Rapid Response Maximize
  federal-state collaboration.
• 13. Technology Expedite consumer notification of
  product recalls.
• 14. Track-and-Trace Expand the use of electronic
  track-and-trace technologies.

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Import Safety at Work

• December 2007 Memoranda of Agreement with
  Chinese authorities to help ensure the safety of
  food, feed, drugs, biologics, and medical devices
  imported from China.
• Sharing information, data and technical expertise
• Establishing an FDA office in China (HHS also
  intends to open a FDA office in India)

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CDER/FDA Import Safety Initiatives

• Prevention
• Promote adoption of Good Manufacturing Practices
  to build safety into the manufacturing and
  distribution processes
• Sharing technical expertise with industry and
  foreign governments

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CDER/FDA Import Safety Initiatives

• Intervention
• Information Technology
• Improving Agency database interaction
• RFID (Radiofrequency identification)
• Holding U.S. Manufacturers accountable
• Increase requirements for active pharmaceutical
  ingredient (API) testing
• Increasing Surveillance Inspections
• Greater emphasis on GMP inspections

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CDER/FDA Import Safety Initiatives

• Response
• Making the Border an Integrated Checkpoint
  (working with Customs Border Patrol)
• Rapid Deployment of For Cause Inspections
• Expanded Use of Track and Trace technologies
• Expanding Laboratory Capacity and Development of
  Rapid Test Methods
• Ramping up cadre of Field and International
  Inspections Staff
• New Authorities Required

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Proposed increase of 09

• Presidential and Congressional Budget Proposals
• Approximately 20 increase
• 404.7 Million
• 1,016 FTEs

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Proposed Legislation

• FOOD AND DRUG ADMINISTRATION GLOBALIZATION ACT
• Authorizes Registration Fees to defray inspection
  costs
• Requires both domestic and foreign firms be
  inspected every 2 yrs
• Requires manufacturer testing of ingredients with
  inadequate documentation before importation
• Requires country of origin labeling
• Provides civil penalties
• Creates dedicated foreign inspectorate

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What Money and Legislation Cant Buy

• Scientific Expertise
• Time to Train Investigators and Reviewers
• Authority over Foreign firms
• Authority over the internet

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Take Home Points

• Funding in the right direction
• Still need better data and analytical systems
• International collaboration is crucial for better
  information and data to make better risk-based
  decisions!

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References

• J Woo, S Wolfgang, H Batista, The Effect of
  Globalization of Drug Manufacturing, Production,
  and Sourcing and Challenges for American Drug
  Safety, Clinical Pharmacology and Therapeutics,
  Vol 83, No 3, March 2008.
• Action Plan for Import Safety a roadmap for
  continued improvement. Report to the President,
  Interagency Working Group on Import Safety, Nov
  2007.
• Preliminary Findings Suggest Weakness in FDAs
  Program for Inspecting Foreign Drug
  Manufacturers, GAO Testimony before the
  Subcommittee on Oversight and Investigations,
  Committee on Energy and Commerce, House of
  Representatives, November 1, 2007.