Vaccine development - Is there a healthy future ? On the interphase of public and private, rich and poor First EPITrain course in advanced epidemiology.

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 29.10.2004Hanna Nohynek, KTL

Starting point

Research and development of clinical productsis - demanding- risky

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

0

10

20

30

40

50

60

90 91 92 93 94 95 96 97 98 99 00 E 01 E

x 1.000 M US $

BUT: vaccines vs. other pharma in market shares

Vaccines

Other pharma

How vaccines are valued

Market value

Societal value

Rappuoli et al. Science 2002

Vaccines

Drugs

The challenge of market economy to development of public health interventions

Public health

Businessprofit

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 bekilled as soon as possible“ -J.Eskola 2/2002GO / NO GO

The processfrom research to practice

Proof of concept

Discovery Research Development Industrialization Use large scale

Phase I Phase II Phase III

Phases of clinical product (vaccine) developmentPhase Numbers Main objective

Preclinical NA ~toxicology

Phase I 10-100 Safety

Phase II 10 - 100 - 999 Immunogenicityand safety

Phase III 1 000 > Efficacy

Post licensure 100 000 >> Efficacyrare AE

A minimum mean 12 years !

An example from the world of pneumococcal conjugates - the starting point in early 1990s

Connaught : 7Pnc Wyeth Lederle : 7-9Pnc CRMAventis Pasteur: 11Pnc TD prot/toxoid GlaxoSmithKline: 11Pnc D proteinMerck: 7Pnc OMP Dutch-Nordic consortium: 4Pnc TT Why do we need so many praprations ?

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

Situation with PCV in June 2002

Proof of concept

Discovery Research Development Industrialization Large scale use

Phase I Phase II Phase III

Wyeth7PCV

Aventis

GSK

? Merck ? DutchNordic

WyethLederle plan on PCV

9PCV Phase III studiesSouth-Africa: VE in nonHIV 85%, in HIV+ 58% The Gambia: pneumonia (2004-5) (mortality ?)

9PCV-MenClicensure year 2003

11>PCV11>PCVMenACYW135Combo-vaccines (aP)

Other companies: PCV R&D is

too risky !

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 antibodiesPnc6B and Pnc19F vs. VE against Acute Otitis Media

FDA: biological, ethically acceptable evidence is needed (I.e. not RCT) for the basis of licensure

An example of the consequence of the FDA decision - are we losing the child when throwing away the washing water ?

Aventis11PncDT + DTwP -> equivalence OK11PncDT + 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”

Situation with PCV in October 2004

Proof of concept

Discovery Research Development Industrialization Large scale use

Phase I Phase II Phase III

Wyeth7PCV

Aventis

GSK

? Merck ? DutchNordic

Prevnar®sold atUSD 50 / dose

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 ….

Gone are the days ….

Well baby clinicHelsinki 1922

Today´s keys to R&D

Good Clinical Practice

Good Manufacturing Practice

Quality Assurance / Control

Consumer safety

Diverging MarketsPrimary Disease

compared to vaccine

MeaslesDiptheria, Pertussis, Tetanus

TB HepatitisBHaemo

philious BPolio

Low Income

Countriesmono wholecell BCG

mono &in combo

with DTPw

in combo with DTPw

OPV

Middle Income

CountriesMMR

wholecell in combo

BCGin combo

with DTPwin combo

with DTPwOPV

High Income

CountriesMMR

accelular in combo

none in combo in comboIPV

in combo

Significant Loss of production

7¢

$10.65

14¢

$15.50

32¢

$9.00

10¢

$8.25

$3.50

$21.38

7¢

Reduction in production - Availability of Basic Vaccines

0

100

200

300

400

500

600

1992

1993

1994

1995

1996

1997

1998

1999

2000

2001

2002

2003

Mill

ion

do

se

s

DTP

BCG

Measles

-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

Panel Discussion in Advanced Course in Vaccinology, 2004

•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

Do combination vaccines limit our possibilities rather than expanding them??

Can the public private interphase work ?

Win - Win

Public health

Business profit

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)

Large scale fermentation and purification of saccharide

44 6B6B 9V9V 1414 18C18C 19F19F 23F23F

7-V7-V

Conjugates are mixed to formulate vaccine

Each type of saccharide is separately activated and conjugated to CRM protein carrier

QC

QC

QC

PolysacchariPolysaccharidede

ProductionProduction

PackagingPackaging

OrderOrderReleaseRelease

ShipShip

22 1144

BulkBulk

ActivationActivationLyophilizaton Lyophilizaton ConjugationConjugation

QualityQualityControlControlReleaseRelease

Filling/Filling/InspectionInspection

QC QC ReleaseRelease& Ship& Ship

66

1616 22 44 11 44

?? ?? ??QualityQualityControlControlReleaseRelease

33

CRMCRMProductionProduction

Sanford, Sanford, NCNC

Pearl Pearl River, NYRiver, NY

1313

Prevenar® : Cumulative Lead TimeUp to 50 Weeks

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

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

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

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

7PCV into EPI in Finland Results: base case and sensitivity analysis of CE

Health care costs

Total costs

Netcosts €/LYS Netcosts €/LYS

Base case 8 125 432 307 092 6 544 069 247 326

Vaccine protection 10 y

6 981 362 238 716 4 848 463 165 785

Best case 3 747 642 44 798 588 427 7 034

Death after pneumonia 8 126 066 177 371 6 190 084 135 144

Price of vaccine 151 € 5 141 010 194 299 3 559 647 134 533

Price of vaccine 95 € 1 974 194 74 613 392 831 14 847

Salo et al Nordic Vaccines, Oslo 2004

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

An alternative: > 1 pneumococcal conjugate vaccines

“Rich” countriesprivate 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 ?

In summary

Vaccines are one of the most cost efficacious ways of preventing disease

Vaccine industry = as any business Market / Market / Market

GCPNew vaccines will not be cheap Constant balancing between public

good vs. individual right

Albert Einstein said:“We cannot solve today’s

problems with the same level of thinking that we were at

when we created them.”