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Vaccine development - Is there a healthy future ?

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

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Vaccine development - Is there a healthy future ?

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  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. Worldwide R&D Spending by Pharmaceutical Companies & Biotechnology Companies x 1.000 M US $ 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

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

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

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

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

  8. The processfrom research to practice Discovery Research Development Industrialization Use large scale Phase I Phase II Phase III Proof of concept

  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 • 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 this many praprations ?  Vulnerability caused by monopoly Lessions taught by the rota vaccine story

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

  13. WyethLederle plan on PCV • 9PCV Phase III studies South-Africa: VE in nonHIV 85%, in HIV+ 58% The Gambia: pneumonia (2004-5) (mortality ?) • 9PCV-MenC licensure year 2003 • 11>PCV • 11>PCVMenACYW135 • Combo-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 Aventis ? Merck ? DutchNordic GSK Wyeth 7PCV Discovery Research Development Industrialization Large scale use Phase I Phase II Phase III Prevnar® sold at USD 50 / dose Proof of concept

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

  21. 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 Reduction in production - Availability of Basic Vaccines

  22. Panel Discussion in Advanced Course in Vaccinology, 2004 Do combination vaccines limit our possibilities rather than expanding them?? • Non-availability of “single” vaccines • Individuals and authorities may want some separate Ag’s • 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

  23. Can the public private interphase work ?

  24. Business profit Public health Win - Win

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

  26. 4 6B 9V 14 18C 19F 23F QC QC QC 7-V Large scale fermentation and purification of saccharide Each type of saccharide is separately activated and conjugated to CRM protein carrier Conjugates are mixed to formulate vaccine

  27. Prevenar®: Cumulative Lead TimeUp to 50 Weeks Sanford, NC Activation Lyophilizaton Conjugation Filling/ Inspection Bulk Packaging Ship CRM Production ? ? ? 13 Quality Control Release Quality Control Release Order Release Pearl River, NY QC Release & Ship 16 3 2 4 1 4 2 4 1 Polysaccharide Production 6

  28. Production Leadtimes and Forecast Why is this important for us to know? Manufacturer’s need long term forecast from us else they will take decision without us. Funding initiates the manufacturer’s 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 Shortage 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 Break even 61 € / 4 doses 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. “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 An alternative: > 1 pneumococcal conjugate vaccines 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 today’s problems with the same level of thinking that we were at when we created them.”

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