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THE WEBCAST WILL THE WEBCAST WILL BEGIN SHORTLYBEGIN SHORTLY
Please dial 888-373-5705 or 719-457-3840 (International callers), and enter passcode 784549# .
You may also listen via streaming audio (your computer speakers). If you experience difficulties with streaming audio, refresh your
screen or dial the number above.
Antiviral Prioritization, Planning Antiviral Prioritization, Planning and Production Capacityand Production Capacity
June 28, 2007
2
Federal Perspective on Antiviral Federal Perspective on Antiviral Federal Perspective on Antiviral Federal Perspective on Antiviral Federal Perspective on Antiviral Federal Perspective on Antiviral Federal Perspective on Antiviral Federal Perspective on Antiviral PrioritizationPrioritizationPrioritizationPrioritizationPrioritizationPrioritizationPrioritizationPrioritization during a Pandemicduring a Pandemicduring a Pandemicduring a Pandemicduring a Pandemicduring a Pandemicduring a Pandemicduring a Pandemic
Alicia M. Fry, MD MPHAlicia M. Fry, MD MPHInfluenza DivisionInfluenza Division
Centers for Disease Control & Prevention Centers for Disease Control & Prevention Atlanta, GAAtlanta, GA
Varies by age Varies by age AmantadineAmantadine, Rimantadine: , Rimantadine: ≥≥1 year1 year
Oseltamivir: Oseltamivir: ≥≥1 years, Zanamivir 1 years, Zanamivir >>5yrs5yrs
Approximately 70Approximately 70--90% effective in 90% effective in preventing influenza illness preventing influenza illness
No interference with immune response to No interference with immune response to trivalent inactivated influenza vaccinetrivalent inactivated influenza vaccine
LAIV should not be given until 48 hours after LAIV should not be given until 48 hours after cessation of antiviralscessation of antivirals
Adamantane ResistanceAdamantane ResistanceAdamantane ResistanceAdamantane ResistanceAdamantane ResistanceAdamantane ResistanceAdamantane ResistanceAdamantane ResistanceMay develop in 2May develop in 2--5 days in 105 days in 10--30% of patients due 30% of patients due to a point mutationto a point mutation
Resistant viruses are crossResistant viruses are cross--resistantresistant
Transmissibility and Transmissibility and pathogenicitypathogenicity unchangedunchanged
Transmission seen in households & institutionsTransmission seen in households & institutions
Dramatic increase in U.S. H3N2 resistanceDramatic increase in U.S. H3N2 resistance
2% during 20032% during 2003--04; 11% during 200404; 11% during 2004--05; 96% during 05; 96% during 20052005--06; 85% during 200606; 85% during 2006--0707
H1N1 resistance in US: 4% during 2004H1N1 resistance in US: 4% during 2004--05, 3% 05, 3% during 2006during 2006--0707
18% in Japanese pediatric treatment study18% in Japanese pediatric treatment study
Often prescribed for >5 daysOften prescribed for >5 days
Reduced Reduced oseltamiviroseltamivir sensitivity among 1sensitivity among 1--2% of 2% of influenza B viruses in Japaninfluenza B viruses in Japan
H5N1 resistanceH5N1 resistance
‘‘MixedMixed’’ H5N1 virus population from 1 treated child showed H5N1 virus population from 1 treated child showed variable oseltamivir sensitivities variable oseltamivir sensitivities
2 of 8 Vietnamese children in recent report had H5N1 virus 2 of 8 Vietnamese children in recent report had H5N1 virus populations demonstrating resistance populations demonstrating resistance
2 Egyptian patients infected with H5N1 virus with reduced 2 Egyptian patients infected with H5N1 virus with reduced sensitivitysensitivity
HHS Goals for StockpilingHHS Goals for StockpilingHHS Goals for StockpilingHHS Goals for StockpilingHHS Goals for StockpilingHHS Goals for StockpilingHHS Goals for StockpilingHHS Goals for Stockpiling81 million courses procured by Federal and 81 million courses procured by Federal and State governmentsState governments
75 million courses to cover treating 25% of the 75 million courses to cover treating 25% of the populationpopulation
6 million to support initial efforts at containment6 million to support initial efforts at containment
SNS goal is 50 million courses: split 80% SNS goal is 50 million courses: split 80% oseltamivir, 20% zanamiviroseltamivir, 20% zanamivir
44 million for pro rata distribution to states from 44 million for pro rata distribution to states from SNS at first sign of a pandemicSNS at first sign of a pandemic
6 million to support containment efforts6 million to support containment efforts
States are expected to purchase remaining States are expected to purchase remaining 31 million, with 25% Federal funding31 million, with 25% Federal funding
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Antiviral Drugs in the SNSAntiviral Drugs in the SNSAntiviral Drugs in the SNSAntiviral Drugs in the SNSAntiviral Drugs in the SNSAntiviral Drugs in the SNSAntiviral Drugs in the SNSAntiviral Drugs in the SNS
5.1 million regimens on hand5.1 million regimens on hand
1.3 million regimens on order1.3 million regimens on order
(capsules and suspension)(capsules and suspension)
Total 5 day treatment regimens* as of 06/01/2007Total 5 day treatment regimens* as of 06/01/2007
* Based on FDA approved treatment regimen
••In addition, 2.9 million regimens of rimantadine, In addition, 2.9 million regimens of rimantadine,
purchased in a season of influenza vaccine shortage, purchased in a season of influenza vaccine shortage,
are still held in the SNS.are still held in the SNS.
2005 HHS Pandemic Plan for 2005 HHS Pandemic Plan for 2005 HHS Pandemic Plan for 2005 HHS Pandemic Plan for 2005 HHS Pandemic Plan for 2005 HHS Pandemic Plan for 2005 HHS Pandemic Plan for 2005 HHS Pandemic Plan for Antiviral UseAntiviral UseAntiviral UseAntiviral UseAntiviral UseAntiviral UseAntiviral UseAntiviral UseNeuraminidase inhibitors preferred because Neuraminidase inhibitors preferred because of resistance issuesof resistance issues
The fall 2005 plan recommends the use of The fall 2005 plan recommends the use of oseltamivir or zanamivir for treatment, oseltamivir or zanamivir for treatment, administered ideally within 48 hours after administered ideally within 48 hours after onset of symptomsonset of symptoms
Treatment preferred over prophylaxis Treatment preferred over prophylaxis because of supply and distribution concernsbecause of supply and distribution concerns
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2005 HHS Pandemic Plan: Use 2005 HHS Pandemic Plan: Use 2005 HHS Pandemic Plan: Use 2005 HHS Pandemic Plan: Use 2005 HHS Pandemic Plan: Use 2005 HHS Pandemic Plan: Use 2005 HHS Pandemic Plan: Use 2005 HHS Pandemic Plan: Use of Antivirals for treatmentof Antivirals for treatmentof Antivirals for treatmentof Antivirals for treatmentof Antivirals for treatmentof Antivirals for treatmentof Antivirals for treatmentof Antivirals for treatmentUntil the SNS target is achieved NVAC Until the SNS target is achieved NVAC recommended priority groups for antiviral recommended priority groups for antiviral treatment should be used for guidancetreatment should be used for guidance
Once the SNS antiviral target is achieved the Once the SNS antiviral target is achieved the goal is to treat all ill personsgoal is to treat all ill persons
2.2. HCWsHCWs with direct patient with direct patient contact: 2.4M contact: 2.4M
3.3. Highest risk outpatients: Highest risk outpatients: 0.7 M 0.7 M
4.4. Pandemic health Pandemic health responders, public safety responders, public safety & government decision & government decision makers: 0.9 Mmakers: 0.9 M
6.6. Outbreak response (PEP Outbreak response (PEP in nursing homes): 2M in nursing homes): 2M
7.7. Prophylaxis of Prophylaxis of HCWsHCWs in in ER, ICU, EMS: 4.8M ER, ICU, EMS: 4.8M
8.8. Pandemic societal Pandemic societal responders & other responders & other HCWsHCWs: 2.7M : 2.7M
9.9. Other outpatients: 47.3M Other outpatients: 47.3M
10.10. Prophylaxis for highest Prophylaxis for highest risk outpatients: 10Mrisk outpatients: 10M
11.11. Prophylaxis for other Prophylaxis for other HCWsHCWs w/patient contact: w/patient contact: 32M32M
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HHS Pandemic Plan: Use of HHS Pandemic Plan: Use of HHS Pandemic Plan: Use of HHS Pandemic Plan: Use of HHS Pandemic Plan: Use of HHS Pandemic Plan: Use of HHS Pandemic Plan: Use of HHS Pandemic Plan: Use of antivirals for containment of antivirals for containment of antivirals for containment of antivirals for containment of antivirals for containment of antivirals for containment of antivirals for containment of antivirals for containment of disease clustersdisease clustersdisease clustersdisease clustersdisease clustersdisease clustersdisease clustersdisease clusters
In special circumstances, state and local In special circumstances, state and local health departments could consider health departments could consider ““targeted targeted antiviral prophylaxisantiviral prophylaxis”” as a communityas a community--based based measure for containing small clusters of measure for containing small clusters of infection with novel strains of influenza.infection with novel strains of influenza.
HHS Pandemic Plan: Use of HHS Pandemic Plan: Use of HHS Pandemic Plan: Use of HHS Pandemic Plan: Use of HHS Pandemic Plan: Use of HHS Pandemic Plan: Use of HHS Pandemic Plan: Use of HHS Pandemic Plan: Use of antivirals for containment of antivirals for containment of antivirals for containment of antivirals for containment of antivirals for containment of antivirals for containment of antivirals for containment of antivirals for containment of disease clustersdisease clustersdisease clustersdisease clustersdisease clustersdisease clustersdisease clustersdisease clustersIncludes case finding, case treatment, Includes case finding, case treatment, identification of close contacts and post identification of close contacts and post exposure prophylaxis exposure prophylaxis
This measure could be implemented in This measure could be implemented in small, wellsmall, well--defined settings such as the defined settings such as the initial introduction of a virus with pandemic initial introduction of a virus with pandemic potential into a small communitypotential into a small community
However, once a pandemic is underway, However, once a pandemic is underway, such a strategy may such a strategy may not not represent an represent an efficient use of limited antiviral supplies efficient use of limited antiviral supplies
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Use of Antiviral AgentsUse of Antiviral AgentsUse of Antiviral AgentsUse of Antiviral AgentsUse of Antiviral AgentsUse of Antiviral AgentsUse of Antiviral AgentsUse of Antiviral Agents
Amount of antiviral agents available to local Amount of antiviral agents available to local health departments will influence priorities health departments will influence priorities for usefor use
Current federal stockpileCurrent federal stockpile
Current state stockpiles (including private sector, Current state stockpiles (including private sector, if applicable)if applicable)
As production capacity of oseltamivir As production capacity of oseltamivir increases and supply increases, additional increases and supply increases, additional uses of antiviral agents can be considered. uses of antiviral agents can be considered.
An interagency working group is working on An interagency working group is working on an update on antiviral guidance, including an update on antiviral guidance, including use for prophylaxisuse for prophylaxis
SummarySummarySummarySummarySummarySummarySummarySummarySummarySummarySummarySummary• Neuraminidase inhibitors are the
preferred agents during a pandemic
• Current HHS antiviral goals are to provide treatment to ALL ill persons during a pandemic persons
• Until federal and state stockpile targets are achieved, prioritization of antiviral agents may be necessary (NVAC prioritization guidelines)
• Discussions regarding use of antivirals for prophylaxis are underway
•• Neuraminidase inhibitors are the Neuraminidase inhibitors are the preferred agents during a pandemicpreferred agents during a pandemic
•• Current HHS antiviral goals are to provide Current HHS antiviral goals are to provide treatment to ALL ill persons during a treatment to ALL ill persons during a pandemic personspandemic persons
•• Until federal and state stockpile targets Until federal and state stockpile targets are achieved, prioritization of antiviral are achieved, prioritization of antiviral agents may be necessary (NVAC agents may be necessary (NVAC prioritization guidelines)prioritization guidelines)
•• Discussions regarding use of antivirals for Discussions regarding use of antivirals for prophylaxis are underwayprophylaxis are underway
Interagency antiviral working group Interagency antiviral working group Interagency antiviral working group Interagency antiviral working group Interagency antiviral working group Interagency antiviral working group Interagency antiviral working group Interagency antiviral working group
Production and Distribution Capacity for Treatment and Prophylaxis Before and During a Pandemic
Mike McGuireVice President, Anti-InfectivesMarketing
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Update of government pandemic stockpiling
• Roche has
– Received orders or letters of intent from the governments of more than
80 countries ,
– Accounting for firm orders of ~215 million treatment courses
0
10
20
30
40
50
60
70
80
90
100
110
2004 2005 2006 2007
num
ber o
f Tam
iflu
trea
tmen
ts in
Mio
Q4
Q1
Q3
Q1
Q2
Published targeted levels of stockpiles > 5%in % of total population based on treatment
0%
10%
20%
30%
40%
50%
60%
Greece
Brazil Ita
ly
Cypru
s
Taiwan
Czech
Repub
lic
Sweden
German
y
Canad
a
Denm
ark
Japan
Algeria
Hong
Kong
Portugal
SpainMalta
United K
ingdomIre
land
United
Sta
tes
Slovenia
Finlan
d
BelgiumMac
au
Norway
Austria
New Z
ealand
Netherla
nds
Singapore
Qatar
Iceland
Switzerla
nd
Kuwait
Luxembo
urg
Australi
a
France
% c
over
age
base
d on
trea
tmen
t
Sources: Media / National pandemic plans (as of April 1, 2007)
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Manufacturing Tamiflu
• Threat of pandemic was a “call-to-action” for rapid capacity expansion
• Tamiflu production is a complex, multi-step process
• Current manufacturing network involves 19 partner companies
• By end-2006, Roche increased production 15-fold versus the levels of production in 2004
• In addition, agreements with 4 third-party manufacturers (China, India, South Africa)
Shikimic acid Epoxide
AzideSmallvessels
Dangerous: toxic and potentially explosive
Drying
Final step
Chemicalplant Filtration
FINAL STEP
Filtration
CHEMICAL CONVERSION
ANISE
E-COLI
•Extraction•Concentration•Purification
•Modification•Removal of biomass
•Extraction of acid
ANISE
E.COLI
1st step
3rd step
Chemical plant Drying
2nd step
Recap: The making of Tamiflu
Active ingredient
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Recap: The making of Tamiflu
Active ingredient
Tamiflu Supply Chain: September 2005 (baseline)
external production partners
Roche
Shikimic acid
Epoxide Azide EncapsulationActiveingredient
15
Production Capacity for Tamiflu 1999-2007
5.5 18 2755
190
0
50
100
150
200
250
300
350
400
450
'99 - '02 2003 2004 2005 2006 2007
Millions of treatmentcourses
External partners help boost capacity further to meet increased demands for pandemic stockpiles
Volumes actually PRODUCED per year
Tamiflu supply chain today
EPX
external production partners
Roche
Shikimic acid
Epoxide Azide EncapsulationActiveingredient
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TamifluTailoring manufacturing output to actual demand
Production well in excess of current order book
Tamiflu Planned approach going forward
• Adapt Tamiflu supply chain output in accordance with demand
• Maintain a buffer stock of intermediates and final active ingredient (oseltamivir)
• Gearing up of production will be triggered by one of two events1. Roche inventories of final active ingredient (oseltamivir) or key
intermediates drop below target levels2. WHO declares pandemic has evolved to phase 4 (human to
human transmission)*
*this could support wave two of a pandemic
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A responsible approach
• Governments worldwide purchase pandemic supplies of Tamiflu at a significantly reduced price
• Roche has demonstrated the ability to produce more than 400 million packs of Tamiflu annually
• Agreements to manufacture supplies for local pandemic use have been granted to companies for China, India and Africa
• BUT… capacity now outstrips demand of government and corporate orders
We Innovate Healthcare
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Case Study: Business-Public Health Partnership in Georgia
James W. Buehler, MDCenter for Public Health Preparedness & Research
– Government responsibilities & public expectations– Potential collaboration with multiple business organizations
• Maintain value proposition: “If we are not creating value for other members, the team will not survive. If we can to that, we can sustain our effort."
• Communication with media & public
Next Step: Community Continuity Atlanta Partnership
(CCAP)
• CDC support for expansion to involve POD exercise with 5-6 metro Atlanta public health districts
• Business-PH-Academic partnership• POD model
– Core PH IC and health team– Staffing by business volunteers
• Small pre-trained group• Just-in-time training
• PH updating POD operations plan• BENS developing business guidance• Hands-On Atlanta recruiting volunteers for mock patients• Potential applicability to pandemic flu dispensing• Evaluation planning
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AcknowledgementsProject advisory group
Metro Atlanta Region, Business Executives for National Security:Conrad "Connie" Busch, Jr., APRJohn H. H. Turner, IIIAnthony Begando
Division of Public Health, GA Dept. of Human ResourcesJ. Patrick O'Neal, MDCalita Richards, PharmD, MPHLee Smith
Study teamJames Buehler MD, Ellen Whitney MPH, Ruth Berkelman MD Full report at BioMed Central Public Healthhttp://www.biomedcentral.com/1471-2458/6/285
FundingAlfred P. Sloan Foundation O. Wayne Rollins FoundationCDC
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