Fotula Fegaras, PhD Senior Director, Regulatory Affairs Sanofi Pasteur Limited, Toronto, Canada

1. The Challenges of Developing, Licensing and Commercialization of New Vaccines - A Global Industry Perspective Fotula Fegaras, PhD Senior Director, Regulatory Affairs Sanofi Pasteur Limited, Toronto, Canada

2. What are Vaccines? • Preparations of antigenic components derived from or related to a pathogen • Stimulate an immune response and confer active protective immunity to the recipient: • Induce humoral response – neutralizing antibody • Induce cell mediated immune response • Induce protective effect through one to three doses • Dose is generally very small (in range of ug to mg) • Immunity lasts for a long time (1 yr to lifetime) Biologicals….not Pharmaceuticals

3. Vaccines Have an Attractive and Unique Business Model • High degree of innovation • High upfront capital investments • Complex manufacturing know-how • Biological competencies • Much longer product lifespan than pharmaceuticals • Specific business model • Long-standing relationships with governments and healthcare authorities

4. Scientific/medical Environment • New Vaccine Targets/Technologies • Compliance Revolution • Increasing Safety Expectations • Business Environment • High Cost/High Risk • Low Investment • Fragility of Supply/Few Suppliers Industry Challenges • Competitive Environment • Other Big Pharmaceuticals • New Biotech Companies • New Technology • Traditional Vaccine Industry • Environment • Frozen Regulatory Environment • Static Products • Static Processes

5. Drivers for Vaccine Development • Marketability • Medical Need • Recommendation of opinion leaders • Technical Feasibility • Regulatory Environment • Public Opinion

6. Drivers for Vaccines • Marketability • Most vaccines need to be profitable so that companies can get a return on their R&D investment • This is critical if companies are going to be able to invest not only in new vaccines but also ones that are not profitable

7. Drivers for Vaccines • Medical Need • This is the main driver for addition of vaccine targets to the pipeline • Not all vaccines are expected to be profitable (e.g. HIV). However, they are pursued because of the overriding importance to global public health

8. Drivers for Vaccines • Recommendation of Opinion Leaders • Since not every target can be worked on, it is important to get the advice of opinion leaders in the scientific and medical communities who help set the priority of the targets • Opinion leaders also play a critical role in helping governments and the public understand the importance and value of vaccines

9. Drivers for Vaccines • Technical Feasibility • A vaccine target, or the immune response to the target that needs to be achieved, may currently not be understood well enough to develop a vaccine • Risk of an inappropriate response having unintended negative effects also needs to be considered • The easy targets have been done (“low hanging fruit”)

10. Drivers for Vaccines • Regulatory Environment

11. Regulatory Challenges Facing Vaccines • Increased perceived concern over the safety of vaccines • Fear of disease vs. fear of vaccine • Collective needs vs. freedom of choice • Expertise vs. right of information • Increased complexity and difficulty of regulatory environment • Lower acceptance of risk. The “zero-risk” attitude • Expanded safety trials • Stringent quality requirements • Expanded post-marketing surveillance • Ever increasing manufacturing standards • Increased cost and length of development • Increased resource drain associated with maintaining marketed products

12. Societal issues can negatively impact immunization uptake

13. Regulatory Challenges Facing Vaccines • Increased perceived concern over the safety of vaccines • Fear of disease vs. fear of vaccine • Collective needs vs. freedom of choice • Expertise vs. right of information • Increased complexity and difficulty of regulatory environment • Lower acceptance of risk. The “zero-risk” attitude • Expanded safety trials • Stringent quality requirements • Expanded post-marketing surveillance • Ever increasing manufacturing standards • Increased cost and length of development • Increased resource drain associated with maintaining marketed products

14. Facing More Stringent Regulatory Constraints Anticipating the regulatory requirements for gaining approval can be challenging Regulatory agencies are requesting increasingly large clinical trial cohorts These trials monopolize large amount of resources The direct result is increasing development costs and longer development time PIP in EU Evolution of Phase III studies Size over the years Rotateq 75,000 FluMist 38,000 Prevnar 39,000 Varivax 11,000 PedvaxHIB™ 6,000 Recombivax HB 1,200 1980 Today

15. Drivers for Vaccines • Public Opinion • This is an important consideration. If people are unwilling to use a vaccine there is little incentive to develop it • If governments and opinion leaders don’t correct inaccurate and misleading information around the benefit and risks of vaccines and vaccination, vaccine developers could be less willing to make the investment needed to bring new vaccines to the market.

16. Misconceptions about Vaccine Safety1 • Vaccines are not safe • Vaccines don’t work • Vaccines are linked to chronic diseases such as autism, multiple sclerosis and Crohn’s disease • Vaccines weaken the immune system • There are many serious side effects from vaccines • Vaccines are not necessary because the diseases are gone • Vaccines contain toxic substances • Some Vaccines aren’t safe because they are released too soon 1. It’s Your Health - Misconceptions about Vaccine Safety, Updated Nov 2009; http://www.hc-sc.gc.ca/hl-vs/iyh-vsv/med/misconception-eng.php Contains Confidential and Proprietary Information of sanofi pasteur

17. Doctors and the public have forgotten about infectious diseases that were a major concern in the past • Polio • Diphtheria • Tetanus • Pertussis • Hib • Measles • Mumps • Rubella

18. Impact of Vaccines on Infectious Diseases in Canada Vaccines reduce the risk and the incidence of infectious diseases * Provisional data from the Division of Immunization & Respiratory Diseases, Health Canada Source: Canadian Immunization Awareness Program

19. Risk Perception • As vaccines reduce the risk of serious infectious diseases - the public focus on the risks of vaccination • As the public demands safer vaccine - regulators and manufacturers work to improve vaccine safety • As efforts to improve vaccine safety increase - vaccine costs increase • As vaccine costs increase – access to vaccines decreases • As access to vaccines decreases – risk of infectious disease increases Hence the need for balance

20. Vaccine Research and Development Academia Disease Target Identified 1-3 yrs 1984 $50 - 80 million Study epidemiology and immunobiological mechanisms 1-5 yrs Industry Market Assessment Select technologies and design HIV Vaccine Pre-clinical evaluations and process development 2-3 yrs 5-6 yrs 1-2 yrs $850 million Clinical evaluations and manufacturing 2009 Regulatory, licensure Government Recommendation (ACIP,NACI) 1-3 yrs 1-5 yrs Immunization Program (NVPO, CIC)

21. Internal Contributors Concept Proof of Concept Product PreCl Ph I Ph II Ph III Dossier Launch Expl Research Development Clinical RegulatoryAffairs Industrialization Production Strategic Mktg. Business Units Business Div. / IP

22. External Contributors Payer, Donors and NGOs Manufacturers Vaccinees Governments / Policy Makers Health Care Providers and Systems The Immunization Community Global Regulatory Environment

23. Vaccine Development From the 18th to 21st Century Most of the vaccine development has occurred in the last two decades. The world has moved from a single vaccine in 1798 to more than 45 vaccines in 2008.

24. Vaccine Development From the 18th to 21st Century Smallpox Vaccine – 1917 Most of the vaccine development has occurred in the last two decades. The world has moved from a single vaccine in 1798 to more than 45 vaccines in 2008.

25. Vaccine Development From the 18th to 21st Century Smallpox Vaccine – 1966 Most of the vaccine development has occurred in the last two decades. The world has moved from a single vaccine in 1798 to more than 45 vaccines in 2008.

26. Vaccine Development From the 18th to 21st Century Smallpox Vaccine – 1966 Most of the vaccine development has occurred in the last two decades. The world has moved from a single vaccine in 1798 to more than 45 vaccines in 2008.

27. Eradication of Smallpox

28. Vaccine Development From the 18th to 21st Century Most of the vaccine development has occurred in the last two decades. The world has moved from a single vaccine in 1798 to more than 45 vaccines in 2008.

29. Vaccine Development From the 18th to 21st Century Polio Vaccine Most of the vaccine development has occurred in the last two decades. The world has moved from a single vaccine in 1798 to more than 40 vaccines in 2000.

30. Vaccine Development From the 18th to 21st Century Polio Vaccine Most of the vaccine development has occurred in the last two decades. The world has moved from a single vaccine in 1798 to more than 40 vaccines in 2000.

31. Vaccine Development From the 18th to 21st Century Polio Vaccine The world has moved from a single vaccine in 1798 to more than 40 vaccines in 2000.

32. Vaccine Manufacturing

33. General Vaccine Production 12 to 24 months Intracellular product Extracellular Product Fermentation – Cell Culture (Fermentor) Cell Disruption (Homogeniser) Primary Recovery (filtration, centrifugation) Upstream Process Purification (Capture, Precipitation, Polishing) Downstream Process Inactivation Conjugation Bulk Antigen Formulation / Sterile Filtration Formulation Filling & Pkg Filling Freeze Drying Labelling & Packaging Regulatory Lot Release

34. Cell Substrate • Viral vaccines need a cell substrate • Validated vaccine approved cell bank • 2 to 3 years to validate • 1 month to grow cells to production level

35. Upstream Process – Growth Phase • The Room • Sterile • Hepa filtered air • Pressure balance • Steam sterilization • Sterile distilled water supply • Gowning procedures • The Ingredients • Everything put into the fermentor must be validated… • Validated cell bank • Validated master seed • Culture medium etc • The Fermentor • Must be self contained • Cleaned and sterilized in place • Computer monitored Quality Regulations: Three levels of barrier to protect the product

36. Upstream Process Primary Recovery • Cell Disruption • Mechanical • Chemical • Clarification • Centrifugation: • Filtration: • Chromatography Clarifying centrifuge

37. Downstream Process • Primary Objective: • Removal of impurities • Maintain biological activity • Secondary Objective: • Clearance of adventitious agents • Inactivation • Chemical or physical • BPL, formaldehyde, heat Filtration

38. Formulation Dilution Adjuvant (e.g. adsorption to Aluminum phosphate Stabilizers Preservatives Blending antigens

39. Filling & Packaging • Sterile filling • Liquid vaccines • Freeze-dried vaccines • Physical Inspection • Labelling & Packaging • Storage • 2-8oC • Frozen • Shipping • Cold chain

40. Quality Control • Identity • Quantity (specific activity) • Purity (quantification of contaminants) • Characterization (size, structure, sequencing) • Activity (Immunology testing, in vitro based system) • Potency in relevant animal model (correlates of protection) • Microbial sterility, pyrogenicity, toxicity, general safety, etc.

41. New concept in cGMP QC QC QC Pack F F Now compliance requires: Demonstration of control and reproducibility of all systems and processes throughout the full manufacturing cycle Dramatic increase in facilities investments, time, data and personnel Q.A. BatchRelease Bulk Dist F/FD Submission to agencies 2 to 4 months *ButFlu : 6 to 7 months 9* to 22 months

42. Regulatory Compliance • Lot Release • Testing of every lot by manufacturer and regulator – test discrepancies • Lot Failures • Increased Regulatory Compliance • Increase production failures as regulations become more stringent • Reduced capacity • Increased production cost • Supply disruptions • Increased Regulatory Penalties • HPFBI; FDA “team biologics” • Large fines; Plant closures

43. Regulatory Compliance • Process Improvements and Process Change • Removal of materials of animal origin • Removal of blood products • Removal of Thimerosal • Increased cost of production • Cold chain disruption • Increased cold chain monitoring – increased loss of shipments • Increased cost of shipping

44. Vaccine safety surveillance post-licensure2 • Formal post-licensure vaccine clinical studies • Post-market surveillance and adverse event reporting • Canadian Adverse Event Following Immunization Surveillance System (CAEFISS) • A passive vaccine safety surveillance system managed by Public Health Agency of Canada • Health care professionals and manufacturers required to report all SAEs following immunization. • Immunization Monitoring Program, ACTive (IMPACT) • An active vaccine safety surveillance system run by Canadian Pediatric Society • Nurse monitors actively search for AEs following immunization at 12 children’s hospitals across Canada 2. Canadian Immunization Guide Seventh Edition – 2006; Canadian Paediatric Society; Vaccine literacy: http://www.cps.ca/english/statements/id/vaccineliteracy.htm *

45. Acknowledgments • Dr. Luc Kuykens, Vice President, Global Regulatory Affairs and R&D QA, sanofi pasteur • Dr. Rob Van Exan, Director Immunization Policy, sanofi pasteur • Ms. Lise Lotter, Manager Regulatory Policy and Intelligence • Ms. Denise Rieker, Director Regulatory Policy and Intelligence, sanofi pasteur