1. New Vaccine Supply and Financing: A Case Study of Combination Vaccines in Developing Countries Viral Hepatitis Prevention Board Meeting Malta October 22-23, 2001

2. Global status of countries using HepB vaccine in their national immunization system, 2001 YesNo August 2001 The boundaries and names shown and the designations used on this map do not imply the expression of any opinion whatsoever on the part of the World Health Organization concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted lines on maps represent approximate border lines for which there may not yet be full agreement. Routine HepB implementation status

3. HepB Combination vaccines: A sample of current developing country users WPRO - Started with monovalent, especially with birth dose, now some adopters with quadrivalent (DTP-hepB) PAHO - Originally not very interested, now adopting combos (quad or pentavalent) AFRO - Two original countries started with monovalent. One now shifting with GAVI, as is most of AFRO, to quadrivalent (DTP- HepB) or pentavalent (DTP-HepB-Hib)

4. Goal The goal of public sector is to ensure that high quality vaccines are developed in adequate capacity and supplied at reasonable prices to meet the priority needs of developing countries. Current Hypothesis The expanded use of combination vaccines in developing countries will have a significant impact on global supply of the individual antigens and programme flexibility.

5. Why this study? This study should provide some clarity regarding the following issues of combination vaccines: –What are the regulatory, supply and programmatic issues impacting availability and use of these vaccines? –What are the implications of these issues? –What can public sector do to maximize the opportunity to introduce new antigens via combination vaccines in developing countries while finding the necessary balance for regulation, supply and acceptance?

6. Combination Vaccines Benefits Fewer number of injections Fewer syringes used - good for injection safety and less waste generation Less thiomersal exposure due to fewer total injections May make the introduction of a new antigen transparent Drawbacks Can limit programme flexibility Present regulatory issues Impact on supply of traditional vaccines One supplier for multiple antigens (supply and price) though that will soon change Can be more expensive than monovalent options Need for cold chain expansion with shift to lower dose.

7. Vaccines Pre-qualified for Sale by UN Agencies by Manufacturer DC/EE is Developing Country or Emerging Economy manufacturers all in purple. Industrial country manufacturers and their products are in blue. All Hep B in this graph is recombinant. There is also one pre-qualified plasma derived Hep B vaccine manufacturer.

8. Regulation and Licensing Status of Combination Vaccines

10. Issues in Regulation of Combination Vaccines Clinical studies Interference between antigens in combinations Adjuvants and their ability to change the immunological characteristics and stability Minimum potency levels must be determined New reference materials need developing Data needed for adverse events analysis

11. Licensing & Oversight of DTwP based Vaccines: EMEA EMEA licenses only products that have a market in Europe: must be re-licensed after five years. Recently re-licensed GSK’s combinations. Spain is now importing significant quantities of DTwP-Hep B - hib combination vaccine for use which will ease concerns that DTwP based combinations are not used in Europe. EC undertakes at WHO request, review of product file, data and facility. EMEA would not license the product, but would delegate authority to the relevant NRA all remaining regulatory activities.

12. DTwP based combination vaccines Supply update Antigen allocation: production and capacity Market characteristics, their effect on demand and resulting predictions

13. 77% of UNICEF’s DTwP supply comes from developing country sources and the amount offered is narrowly meeting demand. As DTwP is siphoned for combination, the supply of DTwP for other programmes could be jeopardized. Source: Unicef Supply Division

14. Availability of Hep B Meanwhile the amount of single antigen Hep B vaccine is about to reach an all time high with the addition of another prequalified Hep B manufacturer to the list, and another likely to follow soon. The only manufacturer making plasma derived is also shifting to recombinant Hep B vaccine production

15. Manufacturer Response to Forecasting Demand Source: GAVI’s Financing Task Force, Forecasting Subgroup and UNICEF Supply Division

17. Market Characteristics, Determining Acceptance and Predictions

18. Vaccine Costs and Premiums for Global Fund purchase for GAVI

19. Determining Acceptance of Combination Vaccines If the antigens in the combination are wanted, the combination has added value. If the combination is affordable, the country is willing to pay more to have the vaccines in combination form. The premium, if reasonable, is worth the benefit (ex. DTwP-HepB). However, the simple availability of a combination vaccine does not automatically make the product of value to the programme (ex. DTwP-HepB-hib in Africa or MMR in Japan).

20. WHO’s Strategic Advisory Group of Experts Recommendations

21.  WHO review the possible combination vaccines and the implications on supply, regulation, presentation, and price and assist countries to assess appropriateness of each combination for their national immunization programmes; consideration of the role of developing country production and the implications of sole source suppliers should be part of this process;

22.  WHO, in working with partners, especially vaccine manufacturers, provide accurate demand forecasting of the various combination vaccines (determined by national immunization programme managers to be beneficial, programmatically feasible, financially sustainable and worth introducing if funding were available).

23.  WHO place priority on the continued action to address and monitor progress with regard to the licensing of vaccines in industrialized countries for use in developing countries.