1. Vaccine development - Is there a healthy future ? On the interphase of public and private, rich and poor First EPITrain course in advanced epidemiology Jurmala Latvia 29.10.2004 Hanna Nohynek, KTL

2. Starting point Research and development of clinical products is - demanding - risky

3. R&D growth accelerated in recent years R&D will grow 9% - 11% per year Nowadays 25.000 trials world wide Source: PhRMA, Ernst & Young Biotech 98 and Deutsche Bank - Alex Brown Estimates Worldwide R&D Spending by Pharmaceutical Companies & Biotechnology Companies x 1.000 M US $

4. BUT: vaccines vs. other pharma in market shares

5. How vaccines are valued Market value Societal value Rappuoli et al. Science 2002 Vaccines Drugs

6. The challenge of market economy to development of public health interventions Public health Business profit

7. Focus of research Public scientific questions proof of concept public health questions vaccine probe study efficacy vs. effectiveness Private (science) licensure sales Unpromising projects will be killed as soon as possible -J.Eskola 2/2002 GO / NO GO

8. The process from research to practice Proof of concept Discovery Research Development Industrialization Use large scale Phase IPhase IIPhase III

9. Phases of clinical product (vaccine) development A minimum mean 12 years !

10. An example from the world of pneumococcal conjugates - the starting point in early 1990s Connaught : 7Pnc Wyeth Lederle : 7-9Pnc CRM Aventis Pasteur: 11Pnc TD prot/toxoid GlaxoSmithKline: 11Pnc D protein Merck: 7Pnc OMP Dutch-Nordic consortium: 4Pnc TT Why do we need so many praprations ?

11. An example from the world of pneumococcal conjugates zConnaught : 7Pnc zWyeth Lederle : 7-9Pnc CRM zAventis Pasteur: 11Pnc TD prot/toxoid zGlaxoSmithKline: 11Pnc D protein zMerck: 7Pnc OMP zDutch-Nordic consortium: 4Pnc TT Why do we need this many praprations ? Vulnerability caused by monopoly Lessions taught by the rota vaccine story

12. Situation with PCV in June 2002 Proof of concept Discovery Research Development Industrialization Large scale use Phase IPhase IIPhase III Wyeth 7PCV Aventis GSK ? Merck ? DutchNordic

13. WyethLederle plan on PCV z9PCV Phase III studies South-Africa: VE in nonHIV 85%, in HIV+ 58% The Gambia: pneumonia (2004-5) (mortality ?) z9PCV-MenC licensure year 2003 z11>PCV z11>PCVMenACYW135 zCombo-vaccines (aP) Other companies: PCV R&D is too risky !

14. Why is the risk of PCV R&D so big ? - bottlenecks FDA of the U.S. : requirement of immunogenic equivalence: WL 7PCV vs. new PCV Researchers: ? Why has FDA chosen an arbitrary serological correlate of protection ? T-cell memory possibly more important than antibody concentrations ! The Finnish experience Pneumococcal antibodies Pnc6B and Pnc19F vs. VE against Acute Otitis Media FDA: biological, ethically acceptable evidence is needed (I.e. not RCT) for the basis of licensure

15. An example of the consequence of the FDA decision - are we losing the child when throwing away the washing water ? Aventis 11PncDT + DTwP -> equivalence OK 11PncDT + DTaP -> equivalence may not be reached -> permission for licensure in the U.S. / EU uncertain So called business decision in Jan 2002: AvP will stop the commercialization of the vaccine

16. Situation with PCV in October 2004 Proof of concept Discovery Research Development Industrialization Large scale use Phase IPhase IIPhase III Wyeth 7PCV Aventis GSK ? Merck ? DutchNordic Prevnar® sold at USD 50 / dose

17. Do we have alternatives ? Could a vaccine manufacturer bypass U.S. / EU registration authorities ? Could registration authorities in third countries accept a product not licensenced in the U.S. / EU ? Yes, but ….

18. Gone are the days …. Well baby clinic Helsinki 1922

19. Today´s keys to R&D Good Clinical Practice Good Manufacturing Practice Quality Assurance / Control Consumer safety

20. Diverging Markets Significant Loss of production 7¢ $10.65 14¢ $15.50 32¢ $9.00 10¢ $8.25 $3.50 $21.38 7¢

21. Reduction in production - Availability of Basic Vaccines -8 of 12 manufacturers stopped producing vaccines -We do have enough vaccine, but the reduction has caused us to lose flexibility; so we (UNICEF, WHO, Governments, Partners) must manage what is available, better

22. Panel Discussion in Advanced Course in Vaccinology, 2004 Non-availability of single vaccines Individuals and authorities may want some separate Ags Mumps-measles Rubella-measles 9-valent Pnc without Meningococcal C Pa Specialization ad hyper-sophistication Manufacturer A Invasive (Pnc, Mnc, Hib) Resp (Flu, Para flu, RSV) Manufacturer B Hepatitis, GIT Manufacturer C Pnc protein vaccine Vulnerability ?! Rich countries may dictate to poor countries the type of combinations Rich countries may dictate the SCHEDULE for poor countries by dictating the combinations Do combination vaccines limit our possibilities rather than expanding them??

23. Can the public private interphase work ?

24. Win - Win Public health Business profit

25. Important to understand Production Leadtimes and Forecast How long does it take to make vaccine? zProduction of a dose: 10-24 months zCapacity Increase: 2-3 years zNew Plant: 5 years for regulatory approval zExisting products, new blend: 1-3 years (DTP- HepB) zCapacity limitations of blending components (e.g. DTwP) zNew regulatory requirements: interruptions min. 2 mo. (Thimerosal)

26. Large scale fermentation and purification of saccharide 46B9V1418C19F23F 7-V Conjugates are mixed to formulate vaccine Each type of saccharide is separately activated and conjugated to CRM protein carrier QC

27. PolysaccharideProduction Packaging OrderRelease Ship 214 Bulk Activation Lyophilizaton Conjugation QualityControlRelease Filling/Inspection QC Release & Ship 6 162414 ? ? ? QualityControlRelease 3 CRMProduction Sanford, NC Pearl River, NY 13 Prevenar ® : Cumulative Lead Time Up to 50 Weeks

28. Production Leadtimes and Forecast Why is this important for us to know? Manufacturers need long term forecast from us else they will take decision without us. Funding initiates the manufacturers behaviour Our expectations should reflect this

29. Is it harmful to public health if there is only one PCV product available ? Probably not, if the manufacturing capacity can meet the public demand and the vaccine proves efficacious in true field conditions

30. U.S. Recommendations for Use of Pneumococcal Conjugate Vaccine All children <2 years Children 2-4 years with Certain chronic illnesses Immunocompromising conditions Consider for all children 2-4 with priority to those 24-35 months Alaska Native, American Indian, African American Attending day care Advisory Committee on Immunization Practices. MMWR 2000

31. Is it harmful to public health if there is only one PCV product available ? Probably not, if the manufacturing capacity can meet the public demand and the vaccine proves efficacious in true field conditions Probably not, if the vaccine price is modest and affordable also to the intermediate and poorer countries

32. 7PCV into EPI in Finland Results: base case and sensitivity analysis of CE Health care costs Total costs Netcosts/LYSNetcosts/LYS Base case8 125 432307 0926 544 069247 326 Vaccine protection 10 y6 981 362238 7164 848 463165 785 Best case3 747 64244 798588 4277 034 Death after pneumonia8 126 066177 3716 190 084135 144 Price of vaccine 151 5 141 010194 2993 559 647134 533 Price of vaccine 95 1 974 19474 613392 83114 847 Salo et al Nordic Vaccines, Oslo 2004

33. Is it harmful to public health if there is only one PCV product available ? Probably not, if the manufacturing capacity can meet the public demand and the vaccine proves efficacious in true field conditions Probably not, if the vaccine price is modest and affordable also to the intermediate and poorer countries No, if it is developed to meet the varied epidemiologic needs of different geographic locations globally

34. An alternative: > 1 pneumococcal conjugate vaccines Rich countries private sector produces vaccines, public sector has more incentives and constructive control than now Less rich, big countries own, publically subvented research, development, and manufacture Small and/or Poor countries ?

35. In summary Vaccines are one of the most cost efficacious ways of preventing disease Vaccine industry = as any business Market / Market / Market GCP New vaccines will not be cheap Constant balancing between public good vs. individual right

36. Albert Einstein said: We cannot solve todays problems with the same level of thinking that we were at when we created them.