16 th February 2011

1. Navigating The Regulatory Maze 16th February 2011 Tim Adetona VoisinConsulting Life Sciences 3 rue des Longs Pres 92100 Boulogne France Tel: +33 1 41 31 83 02 email: adetona@voisinconsulting.com

2. Innovative Healthcare Product Development & Regulatory Strategy

3. Expertise Anticipate, convince and participate in creating forthcoming regulations

4. Products • New classes of productsat borderbetween or combining drugs, biologics, bioactives, medical devices, diagnostics, cosmetics: • Personalized & predictive medicine • Targeted therapies

5. One Multidisciplinary Team +/- 70 connected men & women working as one multicultural, scientific & regulatory team Ph.D, M.D, Pharm.D, M.Sc, Engineers Multilingual: English, French, German, Spanish, Italian, Serbian, Hindi…

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7. Navigating The Nutraceutical Maze • The Nutraceutical Promise • Marketing Objectives • Historical Perspective & Current Status • Differing Classification Questions • Product Positioning Questions • Global Regulatory Frameworks • FSSAI Alignments • Universal Health Claim Considerations • Human Data Elements • Strategic Regulatory Advice

8. The Nutraceutical Promise • Community of supplementusers continue to drive growthimpressively • A 2008 BCC research positions global Nutraceuticalsat 7.4% growth • Projected to hit $176.6 billion by 2013 • Herbalsupplements to 93 billion in 2015 (Global Industries Analysts) • Globalisation of Nutraceuticals has come to stay • Howeverincreasinggrowthtypicallyattractsincreasingregulation • High degree of consumer protection • Promotion of fairtrade, and • Not at the expense of productresearch & innovation • Hence, there are challenges inherentwith the growthpotentials

9. Marketing Objectives • Get products to the market in the shortest time possible • Optimally communicate products’ health benefit to consumers • Achieved within the appropriate regulatory regimen • Preferably, operate the same requirements globally! • Harmonizationfacilitates global trade, R&D, predictability • Pharmas have takenveryhugeharmonizationstepsthroughICH • Global marketdevelopmentsuccess relies on soundknowledge of extensive as well as emerginglegislativeframeworks

10. Historical Perspectives & Status • National regulations used to be “local” in concept and application • Harmonized rules present opportunities for global brands • Regional harmonization are gradually evolving e.g. ASEAN: AFTA • Asia, LAM at various stages of development • EC, USA, Canada, Japan are “stand-alone” at the most • With “work in progress” in key aspects e.g. EU’s • substances other than Vits/Min; • certain aspects of PARNUTS; • Nutrient Profile being a basis for NHCR • Discrepancy exists globally with definition, classification & requirements

11. DifferingClassification Questions • Product designation • Food supplements, dietary Supplements, Vit/Min level, • PARNUTS, FOSHU, Medical Food, • Herbal Product, Botanical product, • Medicinal?, Nutrient?, Ingredient status? • Permmited List for Nutrients, Functional Food, • Probiotic, Prebiotic, • Novel?, Sports food, • Additive permitted, Excipients, • Nutricosmetics, Cosmeceuticals • Market authorization: • registration vs. notification, • duration of procedure, • Life Cycle Management impact

12. ProductPositioning Questions • Regulatory approach questions: • Harmonized procedure • National procedure • Duration & Stringency • Communicating product’s health benefit questions: • NHCR, • Generic Art.13(1), Art.13(5), • Art.14(a) & (b), • Qualified health claims, • SSA, • National rules, • NHPD requirements • Global brand packaging differences: • Label content presentation, • Minimum font size requirements, • Regional RDA, • Mandatory warnings, • Geographical regions (Australia, USA, FDA, EU, Canada, LAM, MEA)

13. Global RegulatoryFrameworks • EU (EFSA, National Authorities) • NHCR 1924/2006 • Nutrition claims/nutrient content • Art. 13 (1) & (5); Art. 14 (a) & (b) • PASSCLAIM criteria • USA (FDA) • Health Claims • NLEA 1990: Authorized Health Claims (SSA – Significant Scientific Agreement) • FDAMA 1997: Authoritative Statements by scientific bodies (not Food Supp) • CHI&BNI 2003: Qualified Health Claims (evidence not as strong as SSA) • Nutrient Claims: NLEA 1990 (similar to EU Nutrition claim) • Structure/Function Claims: DSHEA 1994 (FDA non pre-approveddisclaimer)

14. Global RegulatoryFrameworks • Japan • Foods for special health Use (FOSHU) established from 1991 • Includes processed food products, tablets & capsule forms • Dietary ingredients with beneficial physiological functions in humans • Maintain/promote health; improve health conditions • Similar to other structure/function claims in USA or other functions in Codex Alimentarius • Requires validation of quality, efficacy and safety • Disease risk reduction possible (Ca & osteoporosis; Fä & neural tube defects) • Since 2005, Qualified FOSHU claims (a la FDA) also possible • ASEAN (Association of South East Asian Nations) • Progressive harmonization at the instance of ASEAN Free Trade Agreement (AFTA, 1967) • Definition of Food supplement • Supplements diet to enhance or improve the health function of the human body • Contains one or more of vitamins, minerals, amino acids, enzymes, probiotics, bioactives • Health claim evidence increases from general/nutritional; functional; disease risk reduction

15. Global RegulatoryFrameworks • Korea (KFDA) • Health functional food (HFF) includes • Any form of foods, food supplements with functional ingredients useful to the body • Established in 2002, regulation recognizes Generic HFF (with spec & standards in HFF code) • And product-specific HFF (requires pre-market registration/approval of specific ingredients) • 3 types of claims: nutrient function; other function; reduction of disease (Codex Alimentarius) • Other functions. convincing; probable; or insufficient • China (SFDA) • Functional food: has special health functions or is able to supply vitamins or minerals • Suitable for consumption by special groups of people and regulates human body functions • Toxicity, functionality, stability and hygiene tests are required for pre-market approval • 27 categories of product-specific health claims (function and reduction of disease risk) • Historical/traditional & present-day use data to be provided on herbs

16. Global RegulatoryFrameworks • Latin America • No harmonized provisions on health claims and substantiation • National legislations to be considered separately (Argentina, Brazil, Chile, Colombia, Mexico) • Argentina • No provisions for health claims in the food regulation • Claims on diseases and therapeutic conditions are prohibited • Ads can describe physiological effect of nutrients (vitamins & minerals) on healthy people • Brazil • Food and food supplement labeling is regulated • Positive list on functional and health claims approved in 2008 for 18 nutrients & ingredients • Evidence to support food claims: nutritional, physiological, toxicological trials on animals; biochemical, epidemiological, clinical trials; proof of efficacy through traditional use in the population; and scientific literature • Mexico • Guidelines on nutrition and health claims are based on the Codex Alimentarius

17. FSSAI Alignment • Food Safety and Standards Authorities of India (FSSAI) • Traditionalmedicines not part of Nutraceuticals • USA’sDietarySupplementsincludetraditional and herbalproducts • Canada’s Natural HealthProductsincludetraditional and herbalproducts • EU’s Food Supplements (TraditionalHerbalMedicinesseparatelyregulated) • Japan’s FOSHU (Traditional & HerbalMedicines not part of definition for dietarysupp) • FSSA 2006 listsingredients (& properties) thatcanbeNutraceuticals • Foods for SpecialDietary Uses • May contain plants/botanicals, vit/min, substances of animal origin & dietarysupps • Similar to EU’s Food supplements • ReferencesIndiaRDA • Ca|Vit. D: [EU: 800mg|200IU]; [US/CAN: 1000+mg|600IU]; [Ind: 400/600mg|400IU]

18. UniversalHealth Claim Considerations • Clarify the relationship between the food/constituent and health effect • Clarify valid measurements for the food/constituent and the health effect • Rank all the pertinent scientific data • Verify the quality of each supportive scientific data • Interpret each pertinent study • Consider the totality and the weighing of available scientific evidence • Best substantiated by well-designed human intervention studies. • Demonstrates association between food/constituent and health effect • Observational studies are not typically accepted as strong evidence

19. Human Data Elements • Sufficient characterization of the food component for the claimed effect • Study group is representative of the target population • The use of appropriate controls • Adequate duration of exposure in view of the intended effect • Sufficient characterization of the study group’s background diet and lifestyle • Amount of food/component is consistent with intended pattern of consumption • Compliance monitoring & test of hypothesis • Use of appropriate markers instead of difficult-to-measure true endpoints • Use of biologically valid biomarkers

20. Strategic Regulatory Advice • Determine ideal classification (e.g. EU Ingredient Decision Tree) • Become familiar with pertinent regulatory requirement • Determine optimal regulatory strategy • Investigate possible alternative market authorization route • Review every aspects of the product and pack presentation • Analyze and validate ingredients & formulas in different markets • Conduct data gap analysis for registration/notification & claims • Verify compliant product labeling as per market • Design and compile technical dossier as per chosen strategy

21. More Regulatory Advice • Deploy strategic planning for changing regulatory environment • Invest time & effort behind marketing claim proposition • Investigate appropriate regulatory strategy for claim positioning • Ensure protocol design & study data supports NHCR, HC, QHC, SSA … • Identify & bridge gaps in claim support data • Consider compromise claims wordings as interim strategy • Conduct comprehensive products’ regulatory market readiness • Validate your findings with experienced Experts • Develop & market product on the basis of expert-validated outputs • Plan for Adverse Events Reporting/Vigilance reporting (US, France…)

22. Lest We Forget • The Nutraceuticals market holds much promise • And directly affected by apparent regulatory classification constraints • Passing a health claim application presents another hurdle • Within these challenges are opportunities, and solutions remains in: • Strategic consideration of life-cycle and regulatory alternatives, • Correct application of knowledge of local/national/regionalpeculiarities • Rigorous gap analysis of regulatory market readiness plans • Constructive scientific data positioning and justification • The obvious may not necessarily be the only or optimal pathway • The seeming difficulty may not be a “show-stopper” • To every problem is a solution! We only need to find the right one.

23. Thank You Tim Adetona Voisin Consulting 3 rue des Longs Pres 92100 Boulogne France Tel: +33 1 41 31 83 02 Mob: +41 7 95 49 38 12 email: adetona@voisinconsulting.com