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VACCINES: TECHNOLOGY TRANSFER TO THE DEVELOPING WORLD. John H. Barton Professor Emeritus, Stanford Law School Former Visiting Scholar, NIH Department of Clinical Bioethics. THIS IS A WORK-IN-PROGRESS: PLEASE CRITICIZE, ADVISE, CORRECT, AND SUGGEST, AS NEEDED!

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vaccines technology transfer to the developing world

VACCINES: TECHNOLOGY TRANSFER TO THE DEVELOPING WORLD

John H. Barton

Professor Emeritus, Stanford Law School

Former Visiting Scholar, NIH Department of Clinical Bioethics

slide2
THIS IS A WORK-IN-PROGRESS: PLEASE CRITICIZE, ADVISE, CORRECT, AND SUGGEST, AS NEEDED!

I speak purely for myself and not for Stanford or NIH.

vaccine technology transfer study
VACCINE TECHNOLOGY TRANSFER STUDY
  • Why technology transfer?
    • Technology as engine of growth and science
    • Transfer as affecting access to products for local and global markets
    • Variety of modes changing over time
    • Severe restrictions under current international economic law
  • Why vaccines?
    • Crucial medical intervention
    • Reasonably separable area (and very different history from pharmaceuticals)
    • Interest
vaccine technology transfer outline
VACCINE TECHNOLOGY TRANSFER: OUTLINE
  • Heroic era (1891 => 1930s)
  • National public health: Growth and divergence (193Os = >1990s)
  • Global vaccination programs (1960s => 2000s)
  • Era of privatization and biotechnology (~1990 =>
i heroic era
I - HEROIC ERA
  • Smallpox:
    • Arm-to-arm vaccination – prehistory
    • Jenner – 1798
    • Brazil – 1887 (predecessor of Butantan)
  • Rabies and Pasteur Institutes
    • Pasteur - 1885
    • Pasteur Institutes
      • Dakar – 1896
      • Saigon – 1891
      • Now a network of 29 institutes, including 22 in developing nations
  • Researchers trained at Institut Pasteur
    • Haffkine (Bombay) – 1899
    • Oswaldo Cruz (Rio) – 1900
new vaccines in the heroic days
NEW VACCINES IN THE HEROIC DAYS
  • Typhoid (1896) – Wright (England) and others; trials in India
  • Cholera (1896) – Haffkine, Delhi & Calcutta
  • Plague (1897) – Haffkine, Hongkong?
  • Diphtheria (1923) – Ramon (France) (antitoxin earlier)
  • TB (BCG) (1927) – France, but based partly on work in Saigon
  • Tetanus (1927) – Ramon (France)
  • Pertussis (1933) – Denmark & US
  • Yellow fever (1935) – RF (Lagos & New York); Pasteur (Dakar); trials in Brazil
dynamics of heroic era
DYNAMICS OF HEROIC ERA
  • Scientists had to go where the disease was (Arrowsmith syndrome)
  • Colonial policy (“mission civilisatrice,” “every colony should have its Institut Pasteur”)
  • Public health interest in more sophisticated developing nations (Brazil)
the technology in the heroic days
THE TECHNOLOGY IN THE HEROIC DAYS
  • Production involved small institutes doing both research and production (technology based on animal and flask culture)
  • Technology acquired through personal study (Institut Pasteur)
ii growth and divergence during the mid 20 th century
II - GROWTH AND DIVERGENCEDURING THE MID 20TH CENTURY
  • New vaccines
  • New technologies
  • New regulations
new vaccines
NEW VACCINES
  • Polio (Salk & Sabin)
  • Measles
  • Mumps
  • Hepatitis B
  • Meningococcus
  • Haemophilus influenza
  • Combinations
new technologies
New technologies
  • Culture on chick embryos (Goodpasture, Walter Reed, 1931)
  • Tissue culture (Enders, 1949)
  • Biotechnological production of specific antigens (1980s)
  • Conjugate vaccines (1980s)
  • Plus improved separation methods and improved assays
new regulatory standards
NEW REGULATORY STANDARDS
  • “Jim” and Biologicals Act – 1902
  • Cutter incident – 1955 – led to creation of Division of Biologics Standards in NIH, now in FDA
  • GMP and management of input materials 1963 and 1976
  • Management of air pressure – 1978/87?
  • Documentation and Team Biologics --1990s
meanwhile back in the developing world
MEANWHILE, BACK IN THE DEVELOPING WORLD
  • World War II
  • Independence and conversion of colonial public health systems into national ones, often fighting for limited resources (later on with IMF and World Bank pressures on health budgets)
  • Lack of major scientific research programs comparable to those of the developed world (until Brazil, China, India in about 1980s)
the basic pattern
THE BASIC PATTERN:
  • Many small scale producers (WHO found 74 rabies vaccine producers in 1984, many still using live animals)
  • Frequent GMP problems
  • Did not make most advanced vaccines
    • OPV, not IPV, partly because of WHO pressure
    • Whole-cell pertussis, not acellular
  • Brazil as major exception
brazil 1943 probably making yellow fever vaccine at oswaldo cruz
Brazil – 1943Probably making yellow fever vaccine at Oswaldo Cruz

Lacerda and Mello (2003)

the result approximate statistics dtp coverage 1980
THE RESULT:APPROXIMATE STATISTICSDTP COVERAGE - 1980
  • Industrialized countries 60 %
  • Latin America 38 %
  • South Asia 5 %
  • East Asia 5 %
  • MidEast 25 %
  • Sub-Sahara Africa 5 %

Hadler et al, Vaccination Programs in Developing Countries in Plotkin & Orenstien, Vaccines

technology transfer during the mid and late 20 th century
TECHNOLOGY TRANSFER DURING THE MID AND LATE-20TH CENTURY
  • Early on – probably through personal contact, international meetings, and perhaps international education among scientists
  • Later in period – serious donor efforts:
    • RIVM – Vacsera (1980s)
    • CIDA, Connaught, UNICEF, AID – Pakistan (1981 and 1984)
    • Statens Serum Institut – Razi (1985)
    • Canada plus Oswaldo Cruz – Nigeria (1986)
    • Netherlands, Japan – Bio Farma (1991 & 1992)
    • World Bank – China (mid 1990s)
iii new era of global programs
III - NEW ERA OF GLOBAL PROGRAMS
  • Eradication campaigns
    • PAHO & smallpox – 1950-67
    • WHO - Global smallpox – 1967-77
    • WHO - Polio – 1985-200?
  • EPI – 1974
  • CVI – 1990
  • GAVI – 2000
  • Emergence of UNICEF/Rotary purchase system with tiered pricing
procurement for the global programs
PROCUREMENT FOR THE GLOBAL PROGRAMS
  • Smallpox (1960-77) – encourage local procurement (smallpox animal technology) – developing nations supplied at least 80 % of own needs
  • Polio (1985-200?) – at first entirely developed-nation procurement, some developing-world manufacturers by the 1990s
epi procurement
EPI & PROCUREMENT
  • EPI created in 1974.
  • Latin American Revolving Fund – 1979 - supported by national health ministries.
  • UNICEF procurement system (1978?) – supported by donors, including Rotary and now Gates – with PAHO, now purchases roughly 70 % (by dose) of world’s childhood vaccine near marginal cost.
more on the 1990s revolution in procurement
MORE ON THE 1990s REVOLUTION IN PROCUREMENT
  • EPI/UNICEF initially purchased from developed nations – but faced severe shortages and high prices as suppliers merged and reached capacity limits during 1990s.
  • 10 of 14 developed-world manufacturers partially or totally stopped production of traditional vaccines during 1998-2001 (UNICEF).
  • CVI study of quality and development of matrix in 1993-94.
  • WHO developed a prequalification system – 1989(?).
  • Now UNICEF buys more than 2/3 of its non-OPV vaccines from major developing-nation manufacturers – and small developing-nation manufacturers discouraged
iv contemporary era
IV - CONTEMPORARY ERA
  • Patents and intellectual property
    • TRIPS, stronger developed-world systems
  • Biotechnology
    • Heavy private sector role in developed world, with important public components, especially in vaccines
  • Privatization & emergence of private sector developing-world industry
    • Political and economic thrust throughout world
fiocruz facility 2001
Fiocruz Facility - 2001

http://www.pharmaceutical-technology.com/projects/fiocruz/

economics of developed world vaccine industry
ECONOMICS OF DEVELOPED-WORLD VACCINE INDUSTRY
  • In addition to development cost, very substantial manufacturing fixed cost and difficulty in changing due to regulation
  • Relatively low markup opportunity for mass-use childhood vaccines
  • Patent-based product exclusivity relatively rare, except on newer vaccines and not generally on mass-use children’s vaccines
patent roles
PATENT ROLES
  • Barriers to entry generally based less on patents than on regulatory costs and economies of scale
  • But patents used on components (adjuvants, particular molecules, and processes)
  • Vaccine industry therefore does have to cover royalty costs for intermediates
vaccine patent litigation recent cases
VACCINE PATENT LITIGATION: RECENT CASES
  • Boehringer Ingelheim Vetmedica v. Schering Plough (CAFC 2003) – process for growing and isolating virus
  • Medeva Pharma Ltd. v. Am. Home Prods. (2001) – method of detecting pertussis antigen
  • Embrex v. Service Engineering (CAFC 2000) – method of injecting vaccine into egg
  • Evans Medical v. American Cyanamid (CAFC 1999) – pertussis antigen and vaccine based on it (parallel litigation in Europe)
  • Connaught v. SKB (CAGC 1999) – purification of pertactin
biotechnology and ppps
BIOTECHNOLOGY AND PPPs
  • Developed world biotechnology based on NIH, biotech startups, and license to Pharma
  • For developing world - PPPs
    • Especially HIV, malaria, TB
    • Public/private partnerships
    • Virtual development model
    • Most of research (except clinical trials) in developed world
  • These groups must be concerned about research tool patents, at least insofar as they do research in developed world
  • Patents generally a less serious issue for developing world firms (for traditional childhood vaccines) – but access to trade secret data may be harder!
privatization
PRIVATIZATION
  • Political & fiscal reasons
  • Economic reasons – higher salaries and greater management flexibility
  • Examples
    • VACSERA (Egypt) 1973 and 2002
    • BioFarma (Indonesia) 1997
other motives for creating developing nation manufacturers
OTHER MOTIVES FOR CREATING DEVELOPING NATION MANUFACTURERS
  • Vision of biotechnology as a technology of the future
    • Indian Department of Biotechnology
    • Cuban CIGB
  • Private sector
    • Serum Institute of India 1966
    • Shantha ~ 1990
    • Bharat 1996 (created by Krishna Ella, U of Wis.)
developing nation manufacturers in today s world
DEVELOPING NATION MANUFACTURERS IN TODAY’S WORLD
  • Acquisition by UNICEF favors Europe and several developing-nation manufacturers – and UNICEF is the key international market for the developing-world firms
  • There are now many developing-world manufacturers (20 in DCVMN), of whom 12 have met WHO prequalification standards
the current developing world suppliers to unicef and their technology sources
THE CURRENT DEVELOPING WORLD SUPPLIERS TO UNICEF AND THEIR TECHNOLOGY SOURCES
  • BioFarma (Indonesia, OPV, DPT)
    • Dutch & Japanese governments
  • Fiocruz/Biomanguinhos (Brazil, YF)
    • 1980-83, 2000 Assistance from Japan
    • 1999, 2003 Alliances with GSK
  • Institut Pasteur (Dakar, YF)
    • Long term French input
  • Serum Institute of India (world’s largest producer of measles and DTP, 5th largest vaccine firm)
    • 1996 alliance with SKB
    • 200? NIH, PATH, WHO license for Meningococcal vaccine; also RIVM on Hib technology
  • Shantha Biotechnics (India, OPV, Hepatitis B)
    • Collaboration with Indian research laboratories and support from Oman
some other major developing world producers
SOME OTHER MAJOR DEVELOPING WORLD PRODUCERS
  • Butantan (Brazil)
  • China (Chengdu, Lanzhou, Shanghai, Shenzen)
  • CIGB (Cuba) (WHO prequalified)
  • Instituto Finlay (Cuba, 6 vaccines)
  • Bharat (India) (NIH licensee on rotavirus vaccine, grants from Gates)
examples of other contemporary technology transfer programs
EXAMPLES OF OTHER CONTEMPORARY TECHNOLOGY TRANSFER PROGRAMS
  • Merck license to China (1989)
  • University of Ottawa & Cuba
  • Chiron-Behring joint venture to manufacture rabies vaccine in Gujurat (facility in 1991, venture in 1998
  • WHO and DCVMN (2001) (NIH is a member)
beginnings of globalization e g developing nation supply to developed world
BEGINNINGS OF GLOBALIZATION?(E.G. DEVELOPING-NATION SUPPLY TO DEVELOPED-WORLD)
  • GSK & Cuba – license to use Cuban meningitis B technology – 1999
  • Berna Biotech (Swiss) purchase of GreenCross (Korea) – 2002
  • Wyeth & Bharat – manufacture HiB on license - 2003
reflections technology transfer pattern
REFLECTIONS – TECHNOLOGY TRANSFER PATTERN
  • Phase I (for vaccines, pre 1930) – artisan-level technology, easily copied
  • Phase II (for vaccines, 1930-1995) – growth of many producers at local level, restricted by access to capital rather than to technology
  • Phase III (1995-20??) – globalization and integration, controlled by market structure, regulation, economies of scale in research and production
  • Note that all this depends on
    • The possible scale for the initial technology transfer
    • The timing of the spread compared with global political events such as the current moves to free trade and intellectual property
reflections and pending issues for vaccines i
REFLECTIONS AND PENDING ISSUES FOR VACCINES - I
  • How long will the global donor market be there?
    • Recent dependence on Gates
    • Possibility of donor fatigue – we’re now in a global version of the public health mode
    • Procurement policy?
    • Relevance of growing private market in India (and possibly elsewhere)?
  • The PPP’s:
    • What likelihood of success?
    • What roles for DC or LDC manufacturers?
    • Continued support for procurement as the number of products grows (c.f. problems of integrating Hepatitis B into the EPI package)?
  • Bioterrorism
    • Suspicions of Iran and Cuba
    • Visas
    • Export limitations
    • New development models in the U.S.
reflections and pending issues for vaccines ii
REFLECTIONS AND PENDING ISSUES FOR VACCINES - II
  • Strategic licenses between developed and developing nation firms:
    • Mechanism of technology transfer for serving LDC market – what incentives for each side? Role in access?
    • Possibility of future off-shore production? – importance of labor costs? Feasibility of maintaining quality standards? Trends in economies of scale? Trends in integration?
  • Consolidation on a global scale?
    • Economic or research motivations?
    • Regulation, patents, and access to developed world markets?
    • Choice of markets by developing-country manufacturers?
questions criticisms and suggestions
QUESTIONS, CRITICISMS, AND SUGGESTIONS?

Thank you!

jbarton@stanford.edu