Transcript News from the PCV world

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
- risky
Worldwide R&D Spending by Pharmaceutical Companies
& Biotechnology Companies
x 1.000 M US $
60
R&D growth
accelerated
in recent years
50
40
R&D will grow
9% - 11% per year
30
Nowadays
25.000 trials
world wide
20
10
0
90
91
92
93
94
95
96
97
98
99
Source: PhRMA, Ernst & Young Biotech 98 and Deutsche Bank - Alex Brown Estimates
00 E 01 E
BUT: vaccines vs. other
pharma in market shares
Vaccines
Other pharma
How vaccines are valued
Societal value
Vaccines
Drugs
Rappuoli et al. Science 2002
Market value
The challenge of market economy
to development of
public health interventions
Public
health
Business
profit
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 be
killed as soon as possible“
-J.Eskola 2/2002
GO / NO GO
The process
from research to practice
Discovery
Research
Development
Phase I Phase II
Proof of concept
Industrialization
Phase III
Use
large scale
Phases of clinical product
(vaccine) development
Phase
Numbers
Main objective
Preclinical
NA
~toxicology
Phase I
10-100
Safety
Phase II
10 - 100 - 999
Phase III
1 000 >
Immunogenicity
and safety
Post licensure 100 000 >>
Efficacy
Efficacy
rare 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 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 ?
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
 Lessions
caused by monopoly
taught by the rota vaccine story
Situation with PCV
in June 2002
Aventis
? Merck
? DutchNordic
GSK
Discovery
Research Development
Phase I Phase II
Proof of concept
Industrialization
Phase III
Wyeth
7PCV
Large scale use
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 !
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
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”
Situation with PCV
in October 2004
Aventis
? Merck
? DutchNordic
Wyeth
7PCV
GSK
Discovery
Research Development
Phase I Phase II
Proof of concept
Industrialization
Large scale use
Phase III
Prevnar®
sold at
USD 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 clinic
Helsinki 1922
Today´s keys to R&D
Good Clinical Practice
Good Manufacturing Practice
Quality Assurance / Control
Consumer safety
Diverging Markets
Prim ary Disease
com pared to
vaccine
Low Income
Countries
Middle Income
Countries
High Income
Countries
Measles
Diptheria,
Pertussis,
Tetanus
TB
HepatitisB
Haem o
philious B
Polio
in combo
with DTPw
$3.50
OPV
10¢
mono
wholecell
BCG
mono &
in combo
32¢
with
DTPw
MMR
wholecell
in combo
BCG
in combo
with DTPw
in combo
with DTPw
OPV
MMR
accelular
in combo
none
in combo
in combo
IPV
in combo
14¢
7¢
$15.50 $10.65
Significant Loss of
production
7¢
$9.00 $21.38
$8.25
Reduction in production Availability of Basic Vaccines
600
Million doses
500
400
DTP
300
200
BCG
Measles
100
19
92
19
93
19
94
19
95
19
96
19
97
19
98
19
99
20
00
20
01
20
02
20
03
0
-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
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
Can the public
private
interphase work ?
Win - Win
Public
health
Business
profit
Important to understand
Production 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 (DTPHepB)
 Capacity limitations of blending components
(e.g. DTwP)
 New regulatory requirements: interruptions
min. 2 mo. (Thimerosal)
4
6B
9V
14
18C
19F
23F
Large scale fermentation and purification of saccharide
QC
Each type of saccharide is separately activated
and conjugated to CRM protein carrier
QC
Conjugates are mixed to formulate vaccine
7-V
QC
Prevenar® : Cumulative Lead Time
Up to 50 Weeks
Sanford, NC
Activation
Lyophilizaton
Conjugation
CRM
Production
Pearl River,
NY
6
3
2
4
Packaging
Ship
?
Quality
Control
Release
QC
Release
& Ship
16
Polysaccharide
Production
?
?
13
Filling/
Inspection
Bulk
Quality
Control
Release
1
4
Order
Release
2
4
1
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
Netcosts
Total costs
€/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
Price of vaccine 151 €
8 126 066
5 141 010
177 371
194 299
6 190 084
3 559 647
135 144
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” 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
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
GCP
New 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.”