Reforming GxP for today and tomorrow The general issues Imports vs Safety Driving market & business II. Global Impact Factors Regulation Strategies III. Development of Education Program &Training

1. Demet (DEE) Sag, Ph.D., CRA, GCP
Duke University
Durham, NC
08/15/2017 DR. DEMET SAG 1

2. “Globalization creates real opportunities to collaborate
and leverage our collective expertise and resources.
Investments globally are critical to FDA’s success
domestically”
Mary Lou Valdez
FDA’s Associate Commissioner
for International Programs
08/15/2017 DR. DEMET SAG 2

3. agenda
I. The general issues
 Imports vs Safety
 Driving market & business
II. Global Impact Factors
 Regulation Strategies
III. Development of Education Program &Training
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4. Global challenges & global strategies
There are TWO key issues in Good Regulation Practices:
1. COST factor & rebalancing of the global economy
2. Change of human factor
 Education & Intelligence
 Working power/age & Productivity & Health
As a result, we determine and manage
 Productivity & manufacturing
 Trade for new RD and products
 Environment & Earth Implementation
 Government and the marketplace
• Communication & Regulation
08/15/2017 DR. DEMET SAG 4

5. Global Use of Medicines & Market
Key 2016 number
Spending ~ $1.2 Trillion
 Developed markets decline to 57% of global spending vs.
pharmerging markets increase by 10-30% of global
spending
Brands vs. Generics:
 Spending on Brands $615-645 Billion (Bn)
 Spending on Generics $400-430Bn
The Human Factor:
 Developed Country spending per person $609
 Pharmerging Country spending per person $91
08/15/2017 DR. DEMET SAG 5

6. Global Use of Medicines & Market
Key 2012-2016 Numbers
R&D changes:
 New molecular entity launches 160-185
 Global spending growth CAGR 3-6%
 US spending growth CAGR 1-4%
 Pharmerging spending growth CAGR 12-14%
 “Patent Dividend” $106Bn
08/15/2017 DR. DEMET SAG 6

7. Global Medicine
Significant differences in spending per person will remain
 The top therapy will account for 42% of spending
 An accelerated shift in spending to generics is expected
 Biosimilars adoption will expand, but will remain modest to 2016
 Net spending is expected to be over $1 trillion by 2016
Transformations in Disease Treatment
 Greater availability of existing medicines will transform care
 Availability of new medicines varies by country and disease
 More new medicines will be launched per year (~30-37)
 Treatment will be transformed by new and existing mechanisms
 Treatment for priority diseases will improve, but gaps will remain
08/15/2017 DR. DEMET SAG 7

8. The core therapeutic areas:
1. Cardiology and Metabolic Disorders
2. Gastroenterology
3. Infections
4. Musculoskeletal
5. Neurology
6. Oncology
7. Ophthalmology
8. Respiratory Disorders
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9. Top 20 therapy areas will account for 42% of spending
1. Oncologics $83-88Bn
2. Antidiabedics $48-53Bn
3. Asthma/COPD $44-48Bn
4. Autoimmune $33-36Bn
5. Lipid Regulators $31-34Bn
6. Angiotensin II $22-25Bn
7. HIV anti-virals $22-25Bn
8. Antipsychotics $22-25Bn
9. Vaccines $19-22Bn
10. Immunostimulants $16-18Bn
11. Anti-Ulcerants $15-17Bn
12. Anti-Epilectics $14-16Bn
13. Multiple Sclerosis $14-16Bn
14. Platelet Aggregation Inhibitors $14-16Bn
15. Narcotic Analgesics $14-16Bn
16. Immunosupressants $13-15Bn
17. Contraceptives $13-15Bn
18. Cephalosporins $13-15Bn
19. Antivirals, excluding HIV $12-14Bn
20. ADHD $12-14Bn
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10. Global Spending Growth through 2016
 Annual global spending on medicines will increase from $30Bn in
2012 to $70Bn in 2016
 Absolute growth is forecast to be $220-250Bn over next five years
 Annual global spending growth will increase up to $235-265Bn in
2016 from $240.1Bn in 2007
 Pharmerging markets will grow by $150-165Bn over five years
 Economic development will drive volume growth
 Redistribution of economic developed market growth will be
significant
 Brands, pharmerging markets and generics will drive spending
 Patent expires will reduce brand spending by $127Bn
 U.S. spending growth on medicines will be 1-4%
 Top 5 Europe spending growth will be flat through 2016 around
~2% about ~$50Bn
 Japan’s growth is expected to increase slightly
 Spending growth will be driven by areas of innovation
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IMS Institute for Healthcare informatics

11. Perspective from FDA
GRPs are additional set of guidelines for public
health
 FDA regulated products increasing compared to
decade ago Correspond to a 15% growth rate
 The origin and sources are very diverse arriving from
more than 300,000 facilities in 150 countries
 Quadruple the Volume from 6 million shipments to 24
million shipments in ten years
 Nearly 25cent every dollar spent by Americans are on
products regulated by FDA
08/15/2017 DR. DEMET SAG 11

12. Many FDA Offices and Centers
Play Key Roles in Global Engagement
The Office of International Programs (OIP)
The Office of Regulatory Affairs (ORA)
Office of Medical Products and Tobacco (OMPT)
 The Center for Biologics Evaluation and Research (CBER)
 The Center for Devices and Radiological Health (CDRH)
 The Center of Tobacco Products (CTP)
Office of Foods (OF)
 The Center for Food Safety and Applied Nutrition (CFSAN)
 The Center for Veterinary Medicine (CVM)
The Office of the Chief Scientist (OCS)
08/15/2017 DR. DEMET SAG 12
Source: http:/www.fda.gov/AboutFDA/CentersOffices/default.htm

13. The United States Imports (2002 to 2012)
FOOD Imports
Growth Rate of 10%-15%:
10-15% food imported
 80% of seafood
 50% of fruits
 20% of vegetables
08/15/2017 DR. DEMET SAG 13
Sources: Hamburg, M. 2011. Food and drugs: Can safety be ensured in a time of increased globalization? Presented at the council
of foreign relations NY Symposium, Jan 31.
Huang, S. and Huang, K. 2007. Increased US imports of fresh fruit and vegetables. US Department of Agriculture, Economic
Research Service, FTS-328-01. Revised March 27, 2012, from
http:/www.unitedfresh.org/assets/files/increased%20U.S.%20FFV%20Imports.pdf
Veneziano, D. 2011. Import Stats FY 2002-2010. U.S. FDA, Divisions of Import operations and Policy, Office of Regulatory Affairs,
Washington, DC.

14. The United States Imports (2002 to 2012)
Healthcare Products
 Growth Rate of 10-15%
 80% Active pharmaceutical ingredients (growth
rate 13%)
 Increased over 50% since 2002
 40% finished dosage drugs (growth rate 15%)
 Increased over 50% since 2002
 60% Medical devices (growth rate 10%)
 Increased over 450% since 2002
08/15/2017 DR. DEMET SAG 14
Sources: Hamburg, M. 2011. Food and drugs: Can safety be ensured in a time of increased globalization? Presented at the council
of foreign relations NY Symposium, Jan 31.
Veneziano, D. 2011. Import Stats FY 2002-2010. U.S. FDA, Divisions of Import operations and Policy, Office of Regulatory Affairs,
Washington, DC.

15. Strategies for Global Engagement
1. Increasing International Offices and Posts
(due to series of public health crisis in 2007 and 2008 as of 2011 , in
seven region 13 offices established)
2. Strengthening regulatory capacity
3. Harmonizing science-based standards
4. Leveraging knowledge and resources
5. Implementing risk based monitoring and inspection
6. Communicating for global surveillance, preparedness,
and emergency response
7. Advancing regulatory science
TAKE HOME MESSAGE:
Due to changing RD and advancement in technology
pulling brain power for best possible public health
solutions is necessary in decision making and execution.
08/15/2017 DR. DEMET SAG 15

16. 2. Strengthening regulatory capacity
If countries build their regulatory capacities, everyone will benefit :
1. Improve the safety and value of goods people consume,
2. Empower trade and trust in imports
 Transferring regulatory knowledge and information
1. By international groups, centers, organizations
2. By international scientist exchange program,
3. By catalyzing global and regional networks,
4. By open access online learning tools.
 Strategic investment of capacity building
 International tobacco regulator’s conference
 Inclusion of the customer/patient/end user to the
education process since knowledge is power.
08/15/2017 DR. DEMET SAG 16

17. 3. Harmonizing Standards
 Food Standards
 Codex Alimentarius Commission (Codex)
 United Nation Food and Agriculture (FAO)
 WHO
 Pharmaceutical Standards
 ICH Global Cooperation in Group Members
 Development of regional harmonization initiatives:
 Asia-Pacific Economic Cooperation (APEC)
 Associations of Southeast Asian Nations (ASEAN)
 East African Community (EAC)
 Gulf Cooperation Council (GCC)
 Pan American Network on Drug Regulatory Harmonization
(PANDRH)
 South African Development Community (SADC)
 Standards for Animal Health and Welfare
08/15/2017 DR. DEMET SAG 17

18. 4. Leveraging Resources
The ISSUE: Despite recent improvements FDA does not have the
resources to keep up with ever growing volume since current rates,
it would take an estimated 9 years for FDA for FDA to inspect every
high priority pharmaceutical facility just once.
SOLUTION: Developing International Model
 Frameworks for Partnership
 Foreign Policy Inspections
 Develop global information system
 Expanding intelligence gathering and sharing
 Allocate resources based on risk to create government-government, –industry,
public, -private third party
At the end of the day everything is about COMMUNICATION
08/15/2017 DR. DEMET SAG 18

19. 5. Risk Based Monitoring and Inspection
 Protection against:
 Fraud
 Adulterations
 Security/terrorism
 Risk based strategies to identify products that pose
health risks
 Rapid product screening for contaminants of concern
 Addressing the challenges of internet commerce
08/15/2017 DR. DEMET SAG 19

20. 6. Global Surveillance, Preparedness, and
emergency response
 Global surveillance
 Mobile laboratories
 International Food Safety Authorities Network (INFOSAN)
 European rapid alert system for food and feed (RASFF)
 WHO’s International Health Regulations (IHRs)
 Traceback investigations
 Response to food-born illness outbreaks
 Emergency Operation Center
 Response to international disasters,
 Response to the Pandemic
08/15/2017 DR. DEMET SAG 20

21. 7. Advancing Regulatory Science
 International leadership in DNA Miccroarray research
 Human Genome Project
 Human Protein Project
 Human Microbiome Project
 Advance Cutting Edge Technology
 Nanotechnology for sensitive and fast report
 Prevention of infectious diseases HIV, Meningitis etc
 Ensuring safe applications and use of genetically
modified /engineered technology
 Genetically engineered products first introduced in
1980s to prevent hunger, provide energy, and heal the
world
08/15/2017 DR. DEMET SAG 21

22. The GxP and Regulatory Steps:
1. 21 CFR Part 11
2. Biostatistics
3. Drug Safety: Adverse Event Reporting
4. GCP1: Good Clinical Practice Level 1
5. GCP2: Good Clinical Practice Level 2
6. GLP: Good Laboratory Practice Overview
7. GMP: Good Manufacturing Practice Overview
8. GxP Industry
08/15/2017 DR. DEMET SAG 22

23. Human Factor
 Decreased Birth Rate &Working Age-> Economy GDP
 Trade Flow increased 1.5X faster than GDP
 Capitol Flow increased 3X faster than GDP
 10 % GDP spend on natural resources
 30% more energy need
 Government mitigation into market, pricing drugs,
and healthcare to help private citizens
 Educating 1 chemist in the U.S but 60 in India
 Paying 10% of U.S. graduate in India
 Free education or paid education or
 Free online education like MIT and Harvard
Universities launched
08/15/2017 DR. DEMET SAG 23

24. Understanding the Industry
1. Introduction to the Industry
2. Discovery
3. Drug Development
4. Medical Affairs
5. Business Development
6. Marketing
7. Sales
8. Managed Markets
9. Manufacturing Operations
10. Trade and Distribution
11. Each function-specific course addresses that function’s
12. Role in fulfilling the company’s mission
13. Impact on the company’s profitability and strategic vision
14. Key activities
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25. 1.Business Development
OBJECTIVE: how the Business Development function
helps a company realize its strategic goals.
OUTCOME:
 Explain the link between corporate strategy and
business development strategy
 Describe the reasons pharmaceutical manufacturers
enter into alliances and other business relationships
 Describe in-licensing and out-licensing processes
 Explain common deal types and payment structures
 Discuss how the Business Development function
interacts with other internal functions
08/15/2017 DR. DEMET SAG 25

26. 2. Education in Discovery
OBJECTIVE:
 the discovery process,
 the various technologies employed, and
 the anticipated impact of pharmacogenomics.
OUTCOME:
 Understand the mission of discovery in the industry
 List key steps in the discovery process
 Outline the various means of discovering new compounds
 Discuss technologies that make the process more efficient
 Describe the potential impact of pharmacogenomics
 Define how the Discovery function is typically organized
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27. Expected Outcomes of the Education in
Drug Development
1. the objectives of preclinical research
2. the key phases of clinical development,
 their objectives, and
 the populations studied
3. the “anatomy” of a clinical trial
4. the FDA or global review and approval process
5. how companies typically organize the Clinical
Development function
6. the role of CROs
7. the management role from discovery to the market
08/15/2017 DR. DEMET SAG 27

28. 4. Education to find Business & Industry
1. Describe the industry’s size and scope
2. Articulate the industry’s contribution to global health
3. Explain the differences between
1. Research-based and generics companies
2. Pharma companies and biotechnology companies
4. Describe the regulatory environment governing
the industry
5. Explain the risk-reward relationship that helps drive
the industry
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29. 3. Education in Drug Development
 Explain the preclinical research and clinical
development processes.
 Provide a basic overview of the regulatory pathway to
pharmaceutical approval.
 Understanding the complexity of the diseases with
graduate level life science background possibly an
advanced degree to understand the in and outs from
input data = outcome
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30. 5. Education in Managed Marketing
Environments Health Care- Government-Industry-
OBJECTIVE: work with public and private payers to secure
reimbursement and market access for their products
OUTCOME:
1. Describe discrete payer segments
2. Explain the critical role of private managed care in product
selection
3. Articulate differences among Medicare Parts A, B, C, and D
4. List mechanisms used by payers to influence utilization
5. Define the purpose, structure, and concerns of the Pharmacy &
Therapeutics Committee
6. Explain how and why manufacturers must develop meaningful
clinical and economic arguments to gain reimbursement and
access for their products
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31. 6. Understanding of the Manufacturing
Processes
1. the major components of the manufacturing process
2. the differences between pilot and commercial
manufacturing
3. the differences between manufacture of chemically based
drugs and biologics
4. the rigorous quality controls governing manufacturing
5. the importance of supply chain management
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32. 7. Marketing and Brand Management
maximize a product’s value throughout its life cycle.
 Discuss Marketing’s involvement across the product
life cycle
 Understand the key roles, responsibilities, and
activities of a pharmaceutical brand team
 Name the key elements of a promotional strategy
 Describe the relationship between customer type and
promotional approach
 Describe a variety of strategies for life cycle
management of mature products
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33. 8. Medical Affairs
OBJECTIVE: disseminate unbiased scientific and cost-
benefit information to prescribers and health plans.
OUTCOME:
 Understand the Medical Affairs function’s many responsibilities,
including publication planning,
 deployment of medical science liaisons (MSLs),
 key opinion leader relationship management, and
 management of phase IV trials
 the importance of non-registrational phase IV clinical trials
 how and why health economics and outcomes studies are conducted
 the role of MSLs
 the role that Medical Affairs plays in external medical education
 how Medical Affairs serves as a bridge between a company’s scientific
and commercial functions
08/15/2017 DR. DEMET SAG 33

34. 9. Risk Evaluation and Mitigation Strategies
(REMS)
OBJECTIVE: How to implement a REMS in a way that both
meets compliance requirements and achieves the ultimate
goal: the desired health outcome for a population.
OUTCOME :
 the intended outcomes and goals of a REMS rollout
 the elements and activities involved in a REMS
 how to execute, manage, and assess the effectiveness of a
REMS rollout
 how a REMS will affect various healthcare stakeholders
 the best strategy for addressing each stakeholder
 the stakeholder to take the suggested REMS-related actions
08/15/2017 DR. DEMET SAG 34

35. 10. SALE
OBJECTIVE: the Sales function’s pivotal role in driving
prescribing behavior.
OUTCOME:
 how the Sales and Marketing functions interact
 how sales representatives are trained and compensated
 how sales forces target physicians
 how a sales representative prepares for and executes a
sales call
 various ways in which the Sales function is organized
 key sales support functions
08/15/2017 DR. DEMET SAG 35

36. 11. Trade to the global market
your apple and my apple competition
OBJECTIVE: the various distribution channels through
which pharmaceuticals reach patients.
OUTCOME:
 Describe the processes by which pharmaceuticals reach the
customers who administer or sell them
 Explain the importance of wholesalers
 Describe the “fee-for-service” business model and how it
evolved
 Explain the role of chain warehouses in distribution
 Explain the growing importance of specialty distributors
and specialty pharmacies
 Describe the evolving compensation system for wholesalers
08/15/2017 DR. DEMET SAG 36

37. IN SUMMARY
Global challenges & global strategies
The world will be different ten years from now
 Predicting the issues for solution through sound risk
management and standardization necessary
 Major issues:
 Keeping the COST down
 Minding the human factor & Population
 Increasing PRODUCTIVITY
 Decreasing TIME
 Empowering knowledge with good EDUCATION
 Preserving the Environment
The key is COMMUNICATION
 allocation, intelligence, regulation
08/15/2017 DR. DEMET SAG 37

38. Resources
 FDA
 WHO
 NIH
 IMS Institute for Healthcare Informatics
 US Department of Commerce Pharmaceutical
Price Controls in OECD Countries
 The Centre for International Health Policy (CIHP)
 CIHP On Good Manufacturing Practice (GMP) in
the Pharmaceutical industry
 Personal Communications and Networking
08/15/2017 DR. DEMET SAG 38