New Vaccine Supply and Financing: A Case Study of Combination

Vaccines in Developing Countries

Viral Hepatitis Prevention Board Meeting

Malta

October 22-23, 2001

Global status of countries using HepB vaccine in theirnational immunization system, 2001

Yes No

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

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)

GoalThe 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 HypothesisThe expanded use of combination vaccines in

developing countries will have a significant impact on global supply of the individual antigens and programme flexibility.

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?

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.

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.

DTwP HepB hib DTwP-HepB DTwP-HepB + hib (lyo)measles MR MMRAventis PasteurBiken, J apanBio Farma, IndonesiaChiron, Germany & ItalyCSL, AustraliaGlaxo Smith Kline, BelgiumGreenCross Vaccine, KoreaLucky Goldstar, KoreaMerck and Co.Serum Institute of IndiaSwiss Serum Institute3 DC/EE in process

Regulation and Licensing Status

of Combination Vaccines

Base vaccine Specific Combination Licensing Status

DTwP DTwP-hep B Europe primarily for developing country marketDTwP-Hib Europe primarily for developing country marketDTwP-hep B-Hib Europe primarily for developing country market

DTaP DTaP-hep B Europe and U.S.DTaP-Hib EuropeDTaP-hep B-Hib EuropeDTaP-hep B-Hib-IPV Europe

Measles MMR Europe and U.S. and many countriesMR Europe and U.S. and many countriesMM Europe, U.S., Russia and many countries

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

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.

DTwP based combination vaccines

• Supply update

• Antigen allocation: production and capacity

• Market characteristics, their effect on demand and resulting predictions

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

DTwP

0

100

200

300

400

500

600

Year

Mil

lio

ns

of

Do

se

s

Availability

Demand

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

Manufacturer Response to Forecasting Demand

Source: GAVI’s Financing Task Force, Forecasting Subgroup and UNICEF Supply Division

0

20

40

60

80

100

120

140

DTwP-hep B-Hib DTwP-hep B

Estimated demand 2001-2003 Response to UNICEF RFP

Antigen Re-allocation: Review of One Producer's Response

0

20

40

60

80

100

120

140

DTwP-hep B-Hib DTwP-hep B

# o

f d

oses (

in m

illio

ns)

Estimated demand 2001-2003

Response to UNICEF RFP

Effect of antigen reallocation

Market Characteristics, Determining Acceptance and

PredictionsMarket Characteristics Africa GAVI market Latin America

Financial condition Poor middle income

General programmaticcondition

Weak strong

Programmatic flexibility Limited flexibilityCan choose, more easily, to be

flexible

Ability to make decision tochange usage

Generally the regulatory body isnot qualified to make alternate

usage decisionsRegulatory body is qualified to make

usage decisionsLocal vaccine production of

DTwP, hep B, or Hib None some

Hib disease burdenHigh but other more pressing

problems of concernHigh burden with several studies

already performed

hep B disease burden Very high Lower (priority for Hib above hep B)

PredictionHigh uptake of DTwP-hep B;Not likely to buy anything forwhich there is not a great need.

High uptake of DTwP-Hib;Probably willing to buy combos with

inexpensive extras (like hep B).

Vaccine Costs and Premiumsfor Global Fund purchase for

GAVIVaccine Vial size Cost of vaccine per

dose in 2001 orsoonest available

Premium from 2001-03and expected trend

DTwP 10 dose 0.078 N/Ahep B 10 dose 0.32 N/A

Hib (liq) 1 dose 2.70 N/ADTwP- hep B 10 dose 1.10 + 0.70 to

+ 0.50 decreasingDTwP - Hib (liq) 1 dose 3.00

from 20020

steady DTwP-hep B-Hib (liq) 2 dose 3.50 + 26 to

- 0.14 decreasing

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).

WHO’s Strategic Advisory Group of Experts

Recommendations

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;

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).

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.