Pandemic Influenza Planning: The Reality of Implementation in the Southeast

1
Pandemic Influenza Planning The Reality of
Implementation in the Southeast

• Vaccines Producing an Adequate Supply
• SECEBT
• Emory Conference Center
• 10TH November 2005
• James T. Matthews, Ph.D
• Senior Director
• Health and Science Policy
• Public Policy and Government Relations US

2
Agenda

• Influenza Vaccine Production
• Seasonal and pandemic interrelatedness
• The Pandemic to come dimensions of the problem
• Sanofi pasteur our influenza vaccines and
  global presence - implications
• Importance of Health Authorities Immunization
  Recommendations market growth and expanding
  capacity
• Key Challenges capacity, current technology and
  others
• Meeting the Challenge Sanofi pasteurs Pandemic
  Preparedness Working Group (PPWG)
• Specific Activities within the French (EU)
  Business Unit
• Specific Activities within the US Business Unit
• Integrated overview of sanofi pasteurs PPWG
  Activities and Conclusions

3
Influenza Vaccine Production

• Seasonal Vaccine (Interpandemic) vaccine most
  is inactivated, injectable, most currently
  produced in European Union with some local
  producers, in recent years trivalent
  formulation consisting of an H1N1, H3N2 and B
  strain updated semi-annually (Northern and
  Southern Hemisphere formulations)
• Pandemic vaccine expected to be monovalent
  formulation but will use existing processes and
  capacity there will be no time to either
  develop a vaccine or expand capacity
• The Implication .

4
PANDEMIC PHASES(From WHO Global Influenza
Preparedness Plan - 2005)
5
PANDEMIC PHASES(From WHO Global Influenza
Preparedness Plan - 2005)
6
Pandemic Preparedness and Interpandemic Vaccine
Activities and Production are Intimately Related

• Interpandemic Period
• Pandemic Period
  Pandemic Alert

7
Why the Concern? During the past 100 years,
there have been three major pandemics, and there
are strong signals in recent years of pandemic
potential (epizootics of avian flu)
H5N1
H7N7
H5N1
H9N2
H5N1
H1N1
H3N2
Different Viruses Migratory Birds Domestic Poultry
H2N2
DIFFERENT VIRUSES Migratory Birds Domestic Poultry
H1N1
?
2003
1968
1957
1918
2004/5
1977
1997
1999
1918
1918
50 - 100 millions
1 million
800 000
?
Mortality
Asian Flu
Hong Kong Flu
Spanish flu
1950
1925
1975
2000
8
Flu pandemic the  big picture  through
significant figures
An Influenza Pandemic Overview of the Global
Picture through Significant Figures

• ? 40 M
• ??? M
• 6.2 B
• 300 M doses
• 900 M doses
• 1 or 2 doses?
• ? 2 years
• ? 6 months
• 9 countries

• Estimated Number of deaths in 1918
• Number of people that a 1918 like-pandemic could
  kill
• The current world population
• The worldwide capacity of trivalent current
  vaccine!
• The theoretical equivalent in monovalent but
  issues regarding Yield? / adjuvant? / process
  used? / antigen content?
• Number of doses needed to efficiently prevent
  (compliance / logistics?)
• The expected duration of a pandemic
• Estimation of time between pandemic declaration
  and first doses available
• Number of countries with local production (large
  scale production)
• USA / Canada / Australia / Japan / France / UK
  /Germany / Netherlands / Italy
• 70 of doses produced in Europe
• Substantial pressure on Europe for equitable
  allocation

9
Sanofi pasteur influenza vaccines manufacturing
sites unique challengesInterpandemic bulk
vaccine is produced at two sitesTwo different
vaccines - these vaccines are registered/licensed
in different countries
Val de Reuil (France) Bulk manufacturing
(Vaxigrip?) Filling Packaging (Vaxigrip?)
Marcy lEtoile (France) Filling Packaging
(Vaxigrip?)
Shenzhen (China.) Filling Packaging (Vaxigrip?)
Swiftwater (U.S.) Bulk manufacturing
(Fluzone?) Filling Packaging (Fluzone?)
10
Sanofi pasteurs Global Market Share
2004 Worldwide Market Share (Doses)
Others
8
Shire
3
Immunoprep.

• Our Market share brings with it global
  responsibilities
• Sanofi pasteur does not view pandemic vaccines
  as a business opportunity but a global public
  health challenge

4
Solvay
7
sanofi
pasteur
GSK
48
8
Chiron
10
Japanese
300 Million Doses (estimated Worldwide)
prod.
12
Note Reflects Sanofi Pasteur consolidated sales
plus 100 of Sanofi Pasteur MSD product sales
11
Current Influenza Immunization Rates Are Very
Different Around the World (as of 2003)
(17) Fedson DS. The macro epidemiology of
influenza vaccination in 56 countries, 1997-2003
a report from the macro epidemiology of
influenza vaccination (MIV) Study Group. Vaccine,
2005, In Press, Uncorrected Proof.
12
Public Recommendations by Health Authorities
Accelerate Market Growth
4 M
7.2 M
2 M
1.5 M
13
Market Growth is Dependent on Two Key
FactorsPolicy Recommendations and Reliability
of Supply
Doses (Million)
Source Based on Corporate press releases and
internal estimates 2005 Estimated Mkt Doses
based on internal projections of US market supply
14
We must Focus on Rebuilding the Influenza Vaccine
Marketplace
Total Immunizations and Total Immunization Rate
for All Ages
140,000,000
40
Forecasts --gt
35
120,000,000
30
100,000,000
25
Percent Immunized
80,000,000
Number of Immunizations
20
60,000,000
15
40,000,000
10
20,000,000
5
0
0
1991
1992
1993
1994
1995
1996
1997
1998
1999
2000
2001
2002
2003
2004
2005
2006
2007
2008
2009
2010
2011
Year
Forecast Includes availability adjustments in
2000-2001.
Total shots
Total Population Immunization Rate ("Intended
Behavior")
2003 sanofi pasteur Consumer Study
15
(No Transcript)
16
US Market Outlook is Positive as long as Supply
Supports Market Growth

• Expected to grow from 85M doses to over 150M
  doses by 2010
• Stronger recommendations will drive market growth
• Supply constraints limit recommendation changes

• Manufacturers, Key Policy leaders and the USG are
  in debate on how to increase capacity
• Manufacturers will not expand capacity without
  stronger recommendations to drive demand
• Government is hesitant to strengthen
  recommendations until supply improves

17
Optimizing Coverage during the Interpandemic
Period

• Higher Influenza Immunization Rates are the only
  way to

Prevent more deaths due to influenza each year
Decrease health burden of yearly influenza
epidemics
Increase influenza vaccines production capacity
to ensure that manufacturing capacity is prepared
to meet the demand in a future pandemic
Decrease the risk for genetic reassortment in
humans of animal and human influenza strains by
preventing human influenza virus infections
Provides incentive/rationale to expand
Interpandemic manufacturing capacity
18
Key Challenges regarding Pandemic Vaccine
Development and Production

• Existing Manufacturing Capacity
• The Manufacturing Cycle (most vaccine is
  currently Egg-based)
• Several Unknowns as of today
• Vaccine characteristics
• The pandemic strain
• Quantity of antigen / dose
• Vaccination schedule 1 dose or 2 doses
• Adjuvanted or not?
• Production yield and stability of the pandemic
  strain
• The pandemic vaccine will not be tested at
  large-scale ahead of the pandemic situation, as
  the pandemic strain will not be known in advance
  (safety)

19
Generalized Influenza Vaccine Global Production
Timetable (NH - Representative Year)
Egg supply organization
Egg supply for production
Seed lots
Monovalent batches
Formulation
Filling / Packaging
Packaging documentation
Ref Member State Release
Pharmaceutical file
MA
Clinical trial
Vaccine Delivery
WHO meeting D0 mid Feb
D0
Reagent availabilityEnd of May
Mid May
July/August
D0 - 6 months
20
Pandemic Preparedness within sanofi pasteur -
Meeting the ChallengePandemic Planning Working
Group (PPWG)Specific Activities based in France
(EU) Specific Activities based in the US
Business Unit
21
PPWG Key Activities

• A first draft of a Pandemic Situation Readiness
  Plan had been developed in 2004, and it helped
  organize work flow and define priority activities
  within sanofi pasteur
• Each part of the plan led to specific activities
  in the different areas identified and dedicated
  groups have been put in place in each department.
• The necessity for an Industrial Pandemic
  Emergency Plan has also been highlighted and this
  initiative is now taking place under the
  leadership of the Industrial Product leader
  expected to be completed by Q1, 2006

22
Some Priority Actions for Pandemic Readiness

• Activities Dependent on Vaccine Characteristics
• Determine Vaccine Characteristics
• Prepare for the EMEA registration of a mock-up
  vaccine (core or mock dossier) or license within
  the US
• Pursue EU and US egg-based production projects
  evaluate production at commercial scale and
  stability of bulk vaccine
• Activities Independent of Vaccine Characteristics
• Finalize Industrial Operations Emergency plan and
  develop a full contingency plan for sanofi
  pasteur globally
• Pursue Cell Culture, Adjuvant and Delivery
  Technology Development diversify/develop
  alternatives to egg-based technology and
  intramuscular administration

23
Pandemic Situation Readiness Plan

• Pandemic Situation Work Flow

24
Sanofi pasteurs pandemic preparedness in France

• Research program initiated since 2002
• NIAID research grant Egg-based H5N1 vaccine
  production
• FLUPAN EU/NIBSC contract Cell-based H7N1 vaccine
  production. Originally Vero based. Currently,
  production of H7N1 vaccine in PER.C6? cells
  (Crucell NV) for clinical study with and without
  adjuvant. Currently at preclinical stage with
  safety and immunogenicity Phase 1 study in Q2,
  2006.
• Pilot scale egg-based production of H5N1 vaccines
  since 2004
• Bulk production according to Vaxigrip?
  manufacturing using a scaled-down process in
  BSL2 GMP pilot scale facilities (Marcy lEtoile,
  France)
• Doses released in May 2005
• Large-scale egg-based production pandemic vaccine
  development (in preparation since 2004)
• Large-scale production of several Million doses
  completed in Q3, 2005 in Val de Reuil, France
  will enable sanofi pasteur to respond to some
  Governments requests in Europe
• Large-scale H5N1 vaccine production planned in
  2006

25
Submission of core dossier for mockup
Vaxigrip-like vaccine to EMEA (1)

• First clinical study (Phase 1) based on EMEA
  criteria Start Q2, 2005
• Aimed at selecting the optimal dosage regimen and
  evaluating the safety profile
• In healthy adults (18-40 years), 2 injections
  three weeks apart
• Use A/Vietnam/1194 NIB RG 14 strain provided by
  NIBSC
• Novel unlike conventional reasortants in EU
  issues relating to GMO
• Various dosages, with or without adjuvant (Al
  Hydroxide)
• (7.5, 15, 30 mcg). Results expected Q4,2005

26
Submission of core dossier for mockup
Vaxigrip-like vaccine to EMEA (2)

• Second clinical study (Phase 2) with the selected
  formulation Start Q2, 2006
• Aimed at documenting the safety profile
• Nearly 300 subjects of 18-75 years of age (50 of
  subjects aged over 60 years), 2-dose regimen
• Core mock-up dossier (CTD format) submission in
  2007

27
Pandemic Situation Readiness Planbecause of GMO
Issues within the EU

• Very active in development of Biosafety
  guidelines for large scale production (GMO
  Biosafety) collaboration between producers and
  WHO Biosafety experts objective end of October
  2005 for finalization of the guidelines
• Need to ensure that guidelines are adequate but
  allow production under existing manufacturing
  conditions

28
Pandemic Preparedness Working Group

• Activities in US Business Unit

29
The Next Influenza Pandemic A Cause for Concern

• Estimates of the effect of Pandemic in the US
  alone
• 1-2 yrs in duration
• Overwhelming strain on limited medical resources
  
• 18M 42M outpatient visits
• 314K 734K hospitalizations
• 89K 207K deaths
• 20M 47M additional illnesses
• 71B - 167B in economic damages

The Economic Impact of Pandemic Influenza in the
United States Priorities for Intervention
Martin I. Meltzer, Nancy J. Cox, and Keiji
Fukuda/CDC (2003)
30
The US Government Has Implemented Several Types
of Initiatives to Ensure Preparedness

• US Congress earmarked 100M under FY '05
  appropriations bill for pandemic preparedness
  initiatives actually have spent more than this
  amount to date
• Strategic Reserves of Interpandemic influenza
  vaccine
• Appropriated funding for stockpiles of routine
  pediatric vaccines
• Stockpiles of influenza antivirals

31
Importance of sanofi pasteurs US Business Units
Participation in US Government Pandemic Planning
Initiatives

• US market leader with over 55 market share
  (prior to 2004 Chiron shortage)
• Provides opportunity to prepare company for
  disruption in normal activity
• Strengthens partnership position with government
  in protecting public health
• As only domestic manufacturer, it is critical to
  be responsive to government pandemic preparedness
  initiatives

32
Overview of H5N1 Activities and Pandemic-Related
Activities (US Business Unit only)
NIAID Phase 1
2004 H5N1 Pilot-Scale Contract with NIAID
2004 H5N1 Commercial-Scale Production with
HHS/CDC
2004 Year Round Egg Supply/Contingency Flocks
ContractClinical Development Contract with
HHS/CDC
Contract Modification for Filling 2004 H5N1
Material with Aluminum Hydroxide
2005 H5N1 Commercial-Scale Production Contract
with HHS
H7N7 with/without Alum modification to contract
underway with HHS/CDC
33
Update on Individual Contracts (1)

• DHHS-NIH-NIAID (Development and Production of an
  Investigational Inactivated H5N1 (2004) Influenza
  Vaccine for Use in Phase1/2 Clinical Trials)
• Key Deliverables 4000 single-dose vials (each)
  of two different formulations of Fluzone-like
  vaccine (15mcg and 45mcg/dose, thimerosal-free,
  no adjuvant)
• One of two Contracts awarded in May, 2004
• Sanofi pasteur (as manufacturer) only provided
  CMC information for NIAIDs IND - no direct role
  in first Clinical trial
• Used reverse genetics-derived strain (rg
  A/Vietnam/1203/2004) produced by St.Jude/Webster
  provided to us by NIAID under MTA
• No opportunity to evaluate and compare NIBSC
  (A/Vietnam/1194/2004) seed
• All lots produced in our pilot scale facility -
  approx. 4000 eggs per lot, using scaled-down
  version of commercial process. Yields Low but
  over 4000 doses of each formulation were
  available.
• Current Status vaccine was manufactured in Q4,
  2004 vaccine filled, labeled, packaged, released
  and transferred to NIAID in Q1, 2005. NIAID has
  completed first of several planned clinical
  studies in the VTEUs
• Stability on Bulk and Final Container for
  additional two years

34
Update on Individual Activities (2)

• HHS/CDC (H5N1 Influenza Vaccine Services)
• Sanofi pasteur awarded contract in September,
  2004 for the production of 2 Million doses of
  H5N1 vaccine (dose is operationally defined as
  15mcg/dose or a dose-equivalent)
• As with pilot-scale lots, vaccine produced using
  Webster rg virus (sanofi pasteur early seed
  passes) at commercial scale
• All full scale lots completed in October, 2004.
  Yields relatively low but higher than pilot-scale
• Egg supply at time was not yet transitioned to
  support year round maximized production
• Vaccine is stored as bulk concentrate (2-8oC)
• US Government recently authorized Contract
  amendment to include aluminum hydroxide
  formulation six formulations in preparation
  to be available Q1, 2006 Clinical study to
  begin Q2, 2006
• This is not a standard formulation will require
  Toxicology Study
• Further enhancement of internal
  Medical/Regulatory Team pursue activities
  analogous to core or mock dossier
• Final container and bulk concentrate will be
  assayed for potency for 3 and 2 years,
  respectively

35
Update on Individual Activities (3)

• Egg based contract (HHS/CDC) awarded to sanofi
  pasteur in October, 2004 (Base Year and 4 Option
  years all options have now been exercised)
• Key Deliverables
• Egg-related - restructure flock management to
  assure a year-round supply of embryonated eggs to
  maintain full production and establish
  contingency flocks (final number 20 of current
  flocks), maintain essential supplies important
  positive impact on current commercial-scale
  production
• Produce Investigational lots (3,000 doses dose
  range to be specifically defined) of
  pandemic-like vaccine annually
• Current Status
• All Major Milestones on track (capacity for
  full-scale, year-round production, contingency
  flocks in Q4, 2006)
• DHHS has identified an H7N7 strain (conventional
  reassortant produced at the CDC) for pilot scale
  clinical lots this year (pilot lot production is
  on-going)
• Contract now being amended to include aluminum
  hydroxide formulations

36
Update on Individual Activities (4)

• HHS/CDC-Acquisition of H5N1 Avian Influenza
  Vaccine for the Strategic National Stockpile
• Contract for production of up to 20 Million doses
  of H5N1 awarded Q3, 2005
• Use 2004 viral working seed (strain not updated)
  - but evaluating later seed passes some
  improvement in yields
• Vaccine to be produced at commercial scale prior
  to and without interference with trivalent,
  seasonal vaccine production
• Vaccine currently being produced and to be
  released by end-Q4, 2005/early Q1, 2006
• Vaccine will be held in bulk concentrate for up
  to 2 years or formulated according to results of
  (second) NIAID clinical trial
• Formulated vaccine to be stored and tested for up
  to 2 years

37

Update on Individual Contracts (5)

• Cell RFP (HHS/CDC 2004-N-01102) awarded (US 97M)
  to sanofi pasteur March 31ST, 2005 To
  accelerate development and US licensure of a
  cell-derived influenza vaccine
• Purpose to diversify technology/increase
  capacity
• Initial contract for three year program - based
  on PER.C6? -very aggressive timelines process
  definition and intermediate scale-up, Phase 2
  clinical studies, production of Phase 3 clinical
  lots all milestones on track Phase 1 Q3, 2006
• Early stage of development to be conducted in
  Marcy, leading to US licensure from our Marcy
  intermediate scale facility at 1500 L
• Includes plans for facility design and eventual
  construction in US (actual construction not
  funded)

38
Update on Individual Contracts (6)

• DHHS-ORDC-VB-05-13 Acquisition of H5N1 Avian
  Influenza Vaccine for the Strategic National
  Stockpile
• Contract (HHS0100200500004C) for production of up
  to 20 Million doses of H5N1 awarded Q3, 2005
  (US100 M base)
• Use same or related seed virus as used in 2004
  (strain not updated)
• Vaccine to be produced prior to and without
  interference with manufacturing of trivalent,
  seasonal vaccine at full commercial scale
• Vaccine currently being produced to be
  available in bulk by end-Q4, 2005
• Vaccine will be held in bulk for up to 2 years or
  formulated according to results of (second) NIAID
  clinical trial
• Formulated vaccine to be stored and tested for up
  to 2 years

39
Recent Government and sanofi pasteur Initiatives
to Ensure Pandemic Preparedness

• HHS/CDC (US National Pandemic Plan) to be
  finalized in 2005
• US Congress earmarked 7.1B under FY '06
  appropriations bill for pandemic preparedness
  initiatives - includes funding for construction
• HHS published three pre-solicitation notices
  related to influenza vaccine production RFPs to
  be published on/about 1ST November
• Cell and Recombinant Influenza vaccine production
  (Not applicable)
• Influenza Vaccine Process Improvement
• Dose-sparing strategies adjutants and delivery
  devices (e.g. ID syringe)
• Sanofi pasteur worked closely to educate Congress
  on importance of Pandemic liability
  protection/public compensation legislation

40
Pandemic Preparedness Working Group

• Integrated Overview of sanofi pasteur activities

41
Sanofi pasteur Pandemic Preparedness
Pandemic Preparedness Working Group
Development of detailed global pandemic
preparedness plan business continuity
Awarded Small Scale H5N1 Contract
NIAID Challenge Grant
4 Weeks
Awarded Large Scale H5N1 Contract
Consultation with Global Organizations (WHO,
CDC, EU, IVSTF, EVM)
sanofi pasteur US
sanofi pasteur France/International
EC FluPan
Awarded Egg-Based/Clinical Lot Contract
Awarded Cell Culture Contract
RD Dose SparingAlternative Delivery Adjuvant
Australian, and other possible tenders
EMEA Consultation Pandemic Dossier Preparation
US Diversification Plans
Awarded 2ND Large Scale H5N1 Contract
Formulation and Filling Expansion
Clinical Evaluation of Pandemic Vaccines
US Cell Culture Facility
US Egg Manufacturing Expansion
US FF Expansion
More Vaccine, Shorter Timelines, with more
Diverse Technologies
42
Conclusion regarding Sanofi pasteurs involvement
in Pandemic Preparedness

• Sanofi pasteur and our parent company,
  sanofi-aventis, are fully committed to pandemic
  preparedness through internal preparation, and
  through collaborations with external bodies
  many of these activities report directly to the
  CEO
• Sanofi pasteur actively participates in all
  groups that collaborate, in order to accelerate
  pandemic preparedness
• EVM, IVS International Task Force, IOM,
• Sanofi pasteur is a key partner in all
  initiatives developed by various organizations
  such as WHO, DHHS, NIAID, CDC, the EU and
  welcomes opportunities to share our experience
  with others to help better manage or reduce this
  impending global health threat.