REGULATIONS | ENFORCEMENT | GLOBALIZATION | SECURITY & INTEGRITY

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PART I Regulations: USA Europe Asia International

PART II Enforcement Globalization Supply chain security Case studies Summary

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ENFORCEMENT National enforcement systems Enforcement in the U.S. Guardian & Apothecary Canada Drugs 2012 House Committee Counterfeits 2014 Sanofi Study 2015 Counterfeit drugs in Europe EudraGMDP & EDQM database UK Lipitor 2005 Safety surveillance & Pangea Foreign sourced drugs Chinese scandals Afghanistan Diversion

DQSA • Product identification • Product tracing • Product verification • Detection of suspect products • Response • Notifications • Licensing requirements

FMD • Product identification • Product tracing • End-to-end verification • Wholesaler licensing

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• Globalization of operations

• Manufacturing moving to Asia

• >1,000 GMP-compliant plants in India

• <1,000 Indian and Chinese importers to EU

• Consolidation of pharmaceutical industry

• Consolidation of shipping industry

• R&D shifting to Asia

• Counterfeit drugs come mostly from China ARETE-ZOE, LLC

• Trends: Globalization, Consolidation and Outsourcing

• Business critical operations and manufacturing shifting to Asia

• > 1,000 GMP certified sites in India

• < 1,000 Indian and Chinese plants registered to import to the EU

• Most counterfeit drugs originate from India and China

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54548

13139 12948 11878

8807

7217

6849

6745

4978

4188 3810

3677

2388

827

581

540

457

403 209

118

29

5

1

1

Foodborne Biological Hazards

Monitoring of Marketed Animal Drugs, Feed, and Devices

Compliance: Devices

Drug Quality Assurance

Blood and Blood Products

Food Composition, Standards, Labeling and Econ

Postmarket Assurance: Devices

Technical Assistance: Food and Cosmetics

Pesticides and Chemical Contaminants

Human Cellular, Tissue, and Gene Therapies

Food and Color Additives Petition Review

Bioresearch Monitoring

Project Evaluation: Devices

Colors and Cosmetics Technology

Postmarket Surv. and Epidemiology

Radiation Control and Health Safety Act

Vaccines and Allergenic Products

Unapproved and Misbranded Drugs

Pre-Approval Eval. of Animal Drugs and Food Additives

Tobacco

Molecular Biology and Natural Toxins

Special Field Assignment

Interagency Cooperative Activities

Special Assignment (various)

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Wholesaler licensing | FDA inspections

• State licenses for wholesalers

• Drugs approved in the U.S. from U.S. licensed wholesalers

• State databases of licensed wholesalers

• Most FDA inspections concern foodborne hazards

• 9% of al FDA inspections concern QA of drugs

• Tiny fraction of FDA inspections identified issues with drugs

• Project 56: Drug quality assurances

• Project 63: Health Fraud: Human Drugs ARETE-ZOE, LLC

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EO 13439 | IWG | Operation Guardian

• EO 13439 (July 2007)

• Interagency Working Group on import safety

• Operation Guardian

• ICE-HIS, CBP, FDA, DOJ, FBI, USPIS, CPSC

• Operation Apothecary: illegal internet pharmacies ARETE-ZOE, LLC

. 2001 Canada Drugs

founded

2005 Congressional report

50% intercepted imports originated

from other than declared countries

2011 Canada Drugs purchased

Avastin from Montana Health Solutions

2012 Avastin with no active ingredients reached 76

physicians in 22 U.S. states. FDA investigation launched.

2014 The issue of

counterfeit drugs presented in HR

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Hearing before the Subcommittee on criminal

justice, drug policy and human resources of the

Committee on Government reform House of

representatives 109th Congress

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Causes : • Low-risk high-profit activity

• More complex supply chains

• Spread of the Internet

• International nature hinders enforcement

• Extension to therapeutic drugs (cost-saving efforts)

• 35,000 – 50,000 online pharmacies in the U.S.

• 97% U.S. online pharmacies non-compliant ARETE-ZOE, LLC

Securing supply chain • 2013 DSCSA – Title II of DQSA

• 2014 HR Hearing

• Securing legitimate supply chains

• Popularity of illegal supply chains

• Drug counterfeiting vs. Narcotic trafficking

• Expansion from life-style drugs to therapeutics

• 35-50,000 online sellers, ~97% non-compliant ARETE-ZOE, LLC

Reality: • $ 75 billion (2010)

• $ 200 billion (2014)

• 10% of the pharmaceutical market (2014)

• 96% of all online sale sites illegal

Perceptions: • Not enough information

• Doubts about the risk of exposure

• Drugs purchased online high risk

• Drugs from abroad (Asia)

• Fake drugs are available through retail

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• New regulation on IPR enforcement (2013)

• EC Report on EU Customs enforcement (situation in 2014)

• Top detained articles: cigarettes (35%), toys (10%) and medicines (8%)

• Increasing number of detained small parcels (mail orders)

• China is the main source country

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2242; 30%

10%

9% 6% 5% 4%

4% 4%

Wholesale Distribution Authorizations United KingdomCzechiaPolandFranceNetherlandsBelgiumIrelandSpainPortugalSwedenGermanyDenmarkBulgariaNorwayAustriaGreeceLithuaniaCyprusMaltaFinlandEstoniaLatviaHungaryCroatiaIceland

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“The Big Five” • UK • Germany • France • Italy • Spain

“Highest number of WDAs” • UK • Czech Republic • Poland • France • Netherlands

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0

500

1000

1500

2000

2500

2010 2011 2012 2013 2014 2015 2016

Hungary

Denmark

Iceland

Germany

France

Spain

Estonia

Croatia

Lithuania

Norway

Finland

Cyprus

Belgium

Malta

Netherlands

Ireland

Austria

Portugal

Sweden

Czech Republic

UK

EudraGMDP: GDP certificates

As of April 20, 2016

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EudraGMDP database • Wholesale Distributor Authorizations

• ~6,500 WDAs issued

• Top issuing countries: UK, CZ, PL, FR

• Some EU countries did not enter data

• Good Distribution Practice certificates

• ~2,000 GDP certificates issued in 2014

• ~1,500 GDP certificates issued in 2015

• Top issuing country: MHRA

• GDP non-compliance reports:

• 2 CZ and 1 from Malta

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EDQM databases: • Pharmeuropa

• Pharmeuropa Bio & Scientific Notes

• Knowledge

• Ph. Eur. Reference Standards

• WHO ISA

• WHO ICRS

• Certification

• Standard Terms

• Melclass

Certification database: • Name of the certified substance

• Monograph number

• Certificate holder

• Certificate number

• Issue date

• Expiry date

• Status

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The UK Lipitor scandal (2005): • The most prolific counterfeiting incident occurred in the UK

• First fake medicines in the UK since 1996

• 9 cases of counterfeit meds in UK supply chain in 2004

• 5 of these 9 cases reached patients

Lipitor recall: • Counterfeit packs with genuine batch numbers

• 120,000 packs with copied batch numbers

• ~50% returned packs were counterfeit

• Manufacturer had to cover the costs of recall

• 106 pharmacies affected

• Illegally imported by parallel trader from outside the EU ARETE-ZOE, LLC

Agencies involved:

• INTERPOL

• World Customs Organization

• the Permanent Forum of International Pharmaceutical Crime

• the Heads of Medicines Agencies Working Group of Enforcement Officers

• Pharmaceutical Security Institute (PSI)

• Europol

• Universal Postal Union ARETE-ZOE, LLC

Safety Surveillance

• Lack of safety surveillance in poor countries major factor

• Adverse effects related to the nature of drugs and their use vs. fakes

• High risk countries: China, India, Russia, SE Asia, Af-Pak, Brazil

Operation Pangea

• Purpose is to target the advertisement, sale and distribution of counterfeit drugs and medical devices

• ~100 countries participating, many international organizations involved

• Arrests, seizures and shut down websites

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FOREIGN MADE DRUGS

FDA approved

Manufactured abroad

Imported to the U.S.

FOREIGN SOURCED DRUGS

FDA approved

Manufactured in the U.S.

From imported ingredients

Safety and security issues ARETE-ZOE, LLC

• 40% of U.S. generic and OTC drugs are imported from India

• Many essential and life-saving drugs are made exclusively in China

• Obtaining visa for FDA inspectors to inspect Chinese plants is very difficult

• 80% of all world drugs are manufactured in India and China

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• Foreign made drugs: imported as finished products

• Foreign sourced drugs: manufactured from imported APIs

• 40% of U.S. generic and OTC drugs are imported from India

• 80% of all world drugs are manufactured in India and China

• Many essential drugs are made exclusively in China

• China obstructive with visa for FDA inspectors

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July 2012: Chinese police arrested > 1,900 people in a crackdown on the manufacture and sale of fake medicine

August 2015: Guideline to improve drug safety and quality

SFDA ordered companies to do self-inspections

A month to withdraw applications with data integrity issues

Zheng Xiaoyu:

head of SFDA 1994-2005

executed for corruption in 2007

July 2012: crackdown on the

manufacture and sale of fake medicine

August 2015: Guideline to improve drug safety and quality

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• Impoverished country

• Security situation highly problematic

• High all-cause morbidity & mortality

• Endemic corruption

• Increased demand for medicine

• Financial incentives for illicit imports

• Imports of low quality drugs from Pakistan

• Result: Dramatic increase in imports of poor-quality medicines ARETE-ZOE, LLC

Prevent, detect and investigate the diversion of controlled pharmaceuticals from legitimate sources while ensuring

uninterrupted supply of legitimate drugs.

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mandatory reporting

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• Legitimate medical use, diversion for illicit purpose

• DEA Office of Diversion Control

• Healthcare professionals and pharmacists licensed to dispense controlled substances have to register with the DEA

• International treaties apply to the movement of controlled substances within the U.S. also

• Diversion investigations

• Prevention of chemical diversion

• Theft of controlled substances is subject to mandatory reporting ARETE-ZOE, LLC

• Caution when asked for certain combinations

• Documenting narcotics prescriptions

• Protecting prescription pads

• Keep DEA / license number confidential

• Clearly written prescriptions

• Electronic prescribing

• Adherence to refill policies & return of unused drugs

• Prescription Drug Monitoring Programs (PDMPs)

• Referring patients to specialized practices

• Communicating suspicious behaviors ARETE-ZOE, LLC