Feasibility of Human InfluenzaVaccine Production in Veterinary

Vaccine Production Facilities:FDA Issues

Feasibility of Human InfluenzaVaccine Production in Veterinary

Vaccine Production Facilities:FDA Issues

WHO/OIE/FAO MeetingWHO/OIE/FAO MeetingApril 27, 2006April 27, 2006

Jay Eltermann, CBER/FDAJay Eltermann, CBER/FDA

Overview Overview

Current regulatory mechanismsCurrent regulatory mechanismsAccelerated approval mechanismsAccelerated approval mechanismsEmergency Use AuthorizationEmergency Use AuthorizationRegulatory and technical issuesRegulatory and technical issuesConclusions Conclusions

Applicable Laws and Regulations:Influenza Virus Vaccine

Applicable Laws and Regulations:Influenza Virus Vaccine

Licensed under Section 351(a) of the Public Licensed under Section 351(a) of the Public Health Service ActHealth Service ActHeld to provisions of the Federal Food, Drug and Held to provisions of the Federal Food, Drug and Cosmetic ActCosmetic ActSpecific biologics regulations under 21 CFR 600 Specific biologics regulations under 21 CFR 600 ––680680Applicable drug GMP regulations are under 21 Applicable drug GMP regulations are under 21 CFR 210 & 211CFR 210 & 211IND regulations under 21 CFR 312IND regulations under 21 CFR 312

Review and Licensing Process for Human Vaccine Products

Review and Licensing Process for Human Vaccine Products

Complete evaluation of clinical and safety data Complete evaluation of clinical and safety data ––for use in targeted populationfor use in targeted populationAssessment of the manufacturing processAssessment of the manufacturing processReview of the manufacturing dataReview of the manufacturing dataReview of product testing and CBER testingReview of product testing and CBER testingInspection of manufacturing facilityInspection of manufacturing facilityAfter licensure lots are reviewed and released After licensure lots are reviewed and released under the lot release program (21 CFR 610.1 and under the lot release program (21 CFR 610.1 and 610.2) 610.2)

US Licensed Influenza Virus Vaccine ProductsUS Licensed Influenza Virus Vaccine Products

Currently 4 US licensed manufacturers Currently 4 US licensed manufacturers sanofi pasteur Inc., Chiron and GlaxoSmithKline sanofi pasteur Inc., Chiron and GlaxoSmithKline --inactivated split virus vaccinesinactivated split virus vaccinesMedImmune MedImmune -- live attenuated vaccinelive attenuated vaccine

Combined total potential capacity (for 2006Combined total potential capacity (for 2006--7) of 7) of approximately 100approximately 100--120 million doses of trivalent 120 million doses of trivalent vaccine annually (at 45ug total/dose) vaccine annually (at 45ug total/dose) Current capacity not adequate to meet US Current capacity not adequate to meet US pandemic needs, unless antigen needed per dose pandemic needs, unless antigen needed per dose can be significantly reduced (e.g. adjuvants)can be significantly reduced (e.g. adjuvants)HHS funding increased capacity (but lag time)HHS funding increased capacity (but lag time)

Meeting the Pandemic Flu Vaccine Challenge: FDA Overview and ActionsMeeting the Pandemic Flu Vaccine Challenge: FDA Overview and Actions

Increasing manufacturing diversity and capacityIncreasing manufacturing diversity and capacityDeveloping needed pathways and regulatory processes to Developing needed pathways and regulatory processes to speed vaccine availability speed vaccine availability –– guidanceguidanceAssuring safety and public confidenceAssuring safety and public confidenceFacilitating vaccine manufacturing/availability Facilitating vaccine manufacturing/availability -- current and evolving technologiescurrent and evolving technologies-- produce/evaluate H5N1 and other pandemic vaccinesproduce/evaluate H5N1 and other pandemic vaccines-- antigen sparing advances, adjuvants and deliveryantigen sparing advances, adjuvants and deliveryPandemic prevention strategiesPandemic prevention strategiesGlobal assistance, cooperation, harmonizationGlobal assistance, cooperation, harmonization

Pathways to Speed Availability: Licensure of Pandemic VaccinesPathways to Speed Availability: Licensure of Pandemic Vaccines

FDA views a pandemic strain used in a licensed FDA views a pandemic strain used in a licensed manufacturing process as a strain changemanufacturing process as a strain change

-- For licensed manufacturers (inactivated or For licensed manufacturers (inactivated or live vaccine) would not be treated as a live vaccine) would not be treated as a new new vaccinevaccine but as a clinical supplement to the but as a clinical supplement to the application, subject to expedited review:application, subject to expedited review:Dosing and immunogenicity, safety if as higher dosesDosing and immunogenicity, safety if as higher doses

Either a wild type or reassortant virus (including Either a wild type or reassortant virus (including reverse genetics) can be usedreverse genetics) can be used

Pathways to Speed Availability:Accelerated Approval

Pathways to Speed Availability:Accelerated Approval

FDA considers there to be a short supply and FDA considers there to be a short supply and influenza is a serious and sometimes lifeinfluenza is a serious and sometimes life--threatening diseasethreatening diseaseHIHI antianti--HAHA antibody levels likely surrogateantibody levels likely surrogateAccelerated approval based on immunogenicityAccelerated approval based on immunogenicityGSK data generated/reviewed and approved very GSK data generated/reviewed and approved very rapidly enhancing annual supply and pandemic rapidly enhancing annual supply and pandemic preparedness preparedness -- 900 person safety/immunogenicity study 900 person safety/immunogenicity study planned/reviewed/enrolled in monthplanned/reviewed/enrolled in month

Pathways to Speed Availability:Accelerated Approval

Pathways to Speed Availability:Accelerated Approval

Indicates that with preparation, substantive and Indicates that with preparation, substantive and needed data can potentially be rapidly obtained needed data can potentially be rapidly obtained even in an evolving pandemic situationeven in an evolving pandemic situation

We can consider similar approaches for most We can consider similar approaches for most pandemic vaccines, including adjuvanted, cell and pandemic vaccines, including adjuvanted, cell and recombinantrecombinant

Draft Guidance for IndustryDraft Guidance for Industry

Two documents issued on March 2, 2006Two documents issued on March 2, 2006Clinical data needed to support licensure of Clinical data needed to support licensure of trivalent inactivated influenza vaccinestrivalent inactivated influenza vaccinesClinical data needed to support licensure of Clinical data needed to support licensure of pandemic influenza vaccinespandemic influenza vaccines

Considerations for Human Vaccine Products for emergency useConsiderations for Human Vaccine Products for emergency use

Need to have product available in large Need to have product available in large quantities in a very short period of timequantities in a very short period of time

-- to be balanced against to be balanced against --Use in hundreds ofUse in hundreds of millions of healthy millions of healthy individuals (including children) individuals (including children) with limited clinical or manufacturing with limited clinical or manufacturing informationinformation

Potential Manufacturing Options in an EmergencyPotential Manufacturing Options in an Emergency

Increase the capacity of current licensed Increase the capacity of current licensed manufacturers by utilization of other approved manufacturers by utilization of other approved manufacturing facilities under contractual manufacturing facilities under contractual arrangementsarrangementsUse of human vaccine products under IND or Use of human vaccine products under IND or EUA EUA for which there is some clinical experience for which there is some clinical experience supporting safety and immunogenicity but which supporting safety and immunogenicity but which are not yet licensedare not yet licensedUse of veterinary vaccine product facilities to Use of veterinary vaccine product facilities to manufacture human flu vaccine products under manufacture human flu vaccine products under IND or EUAIND or EUA

Use of Veterinary Vaccine Manufacturing Facility - ConsiderationsUse of Veterinary Vaccine Manufacturing Facility - Considerations

Production issues such as the number of doses that Production issues such as the number of doses that could potentially be manufacturedcould potentially be manufacturedNeed to assess potential issues from the veterinary Need to assess potential issues from the veterinary products manufactured in the facility facility that products manufactured in the facility facility that could impact on human flu vaccine (what host could impact on human flu vaccine (what host cells being used; adventitious agents ) cells being used; adventitious agents ) Need to assess the impact on veterinary products Need to assess the impact on veterinary products by bringing human vaccine components into by bringing human vaccine components into veterinary product facilityveterinary product facilityNeed to assess the ability to transfer the Need to assess the ability to transfer the manufacturing process to the veterinary vaccine manufacturing process to the veterinary vaccine facilityfacility

Use of Veterinary Vaccine Manufacturing Facility - ConsiderationsUse of Veterinary Vaccine Manufacturing Facility - Considerations

Need to assess the facility/systems/equipment and Need to assess the facility/systems/equipment and the controls in place to manufacture human flu the controls in place to manufacture human flu vaccine according to CGMPsvaccine according to CGMPsNeed to assess the inactivation of adventitious Need to assess the inactivation of adventitious agents and cleaning of manufacturing areas and agents and cleaning of manufacturing areas and equipmentequipmentPotential use of dedicated equipment for human Potential use of dedicated equipment for human flu vaccine campaignsflu vaccine campaigns

Tools to Speed Product Availability and Facilitate Evaluation/ApprovalTools to Speed Product Availability and Facilitate Evaluation/Approval

Early and frequent consultation between Early and frequent consultation between sponsor, end user (if different), and FDAsponsor, end user (if different), and FDAFast trackFast trackPriority reviewPriority reviewAccelerated approval Accelerated approval –– surrogatesurrogateApproval under Approval under ““Animal RuleAnimal Rule””Availability for emergency use under IND Availability for emergency use under IND or Emergency Use Authorization (EUA)or Emergency Use Authorization (EUA)

Product Availability under INDProduct Availability under IND

Facilitated implementation to use products under IND in Facilitated implementation to use products under IND in an emergency (e.g., smallpox or anthrax release)an emergency (e.g., smallpox or anthrax release)-- ““StreamlinedStreamlined”” IND IND –– flexible requirementsflexible requirements-- Informed consent required per regulationsInformed consent required per regulations

-- Frequently significant uncertainty re: risks/benefitsFrequently significant uncertainty re: risks/benefits

-- Potentially cumbersome for widespread usePotentially cumbersome for widespread use

Emergency Use Authorization (EUA):

Emergency Use Authorization (EUA):

Sec. of HHS can declare emergency after Sec. of Sec. of HHS can declare emergency after Sec. of Defense, Homeland Security, or HHS determines Defense, Homeland Security, or HHS determines an emergency (or potential for one) exists, an emergency (or potential for one) exists, affecting national securityaffecting national securitySec. of HHS (FDA) can authorize use of product:Sec. of HHS (FDA) can authorize use of product:-- For serious or lifeFor serious or life--threatening conditionthreatening condition-- No adequate, approved, available alternativeNo adequate, approved, available alternative-- Known & potential benefits outweigh known & Known & potential benefits outweigh known &

potential riskspotential risksEUA granted for up to 1 yr: can be renewedEUA granted for up to 1 yr: can be renewed

Groundwork is Needed for Broad Emergency Use Under IND or EUAGroundwork is Needed for Broad Emergency Use Under IND or EUA

Product may be used very widely in multiple populationsProduct may be used very widely in multiple populationsTherefore, should have reasonable evidence of safety and Therefore, should have reasonable evidence of safety and support for efficacy or likely surrogate such as support for efficacy or likely surrogate such as immunogenicityimmunogenicityPrimary time challenge in development is proof of principle Primary time challenge in development is proof of principle and making product consistently and making product consistently -- not clinical studies or not clinical studies or reviewreviewThis should be done before emergency (or preThis should be done before emergency (or pre--pandemic/epidemic) wherever possible pandemic/epidemic) wherever possible Managed, prioritized, funded processes needed to identify and Managed, prioritized, funded processes needed to identify and develop candidates, assure data will be available to support usedevelop candidates, assure data will be available to support usein an emergencyin an emergency

Risk/Benefit for Emergency Use ProductsRisk/Benefit for Emergency Use ProductsFDA assesses risk/benefit for each product/use and the FDA assesses risk/benefit for each product/use and the situation on the ground at that timesituation on the ground at that time-- Treatment: for otherwise untreatable, serious illness, Treatment: for otherwise untreatable, serious illness,

reasonable to tolerate significant riskreasonable to tolerate significant risk-- Prevention: if given to well individuals, balance shifts, Prevention: if given to well individuals, balance shifts,

especially if preespecially if pre--exposure (or preexposure (or pre--outbreak)outbreak)Lack of efficacy can be a safety issueLack of efficacy can be a safety issue-- Something is not always better than nothingSomething is not always better than nothing-- Ineffective therapy can inhibit development of effective Ineffective therapy can inhibit development of effective

therapiestherapiesAll such products need objective and effective risk All such products need objective and effective risk communicationcommunication

Facility and production concerns for the manufacture of human products in veterinary product facilities

Facility and production concerns for the manufacture of human products in veterinary product facilities

Potential for the introduction of adventitious Potential for the introduction of adventitious agents into human and/or subsequent veterinary agents into human and/or subsequent veterinary productsproductsAbility to decontaminate facility/equipment after Ability to decontaminate facility/equipment after campaignscampaignsAppropriate systems and controls in placeAppropriate systems and controls in placeCrossCross--contamination between products contamination between products Technology transfer issuesTechnology transfer issues

Urgent Use? - Relevant Lessons of Swine FluUrgent Use? - Relevant Lessons of Swine Flu

Communication re: benefit/risks criticalCommunication re: benefit/risks critical-- Includes uncertainty of pandemic/epidemic Includes uncertainty of pandemic/epidemic --

as vaccine benefit depends on itas vaccine benefit depends on it-- Likely better in nonLikely better in non--crisis or routine situation crisis or routine situation

-- primingprimingAbility and process to reevaluate changing Ability and process to reevaluate changing situationssituationsPublic's safety concerns and expectations are Public's safety concerns and expectations are important and significant (and even more so important and significant (and even more so today) and can affect, and even derail, today) and can affect, and even derail, vaccination plansvaccination plansImportance of safety monitoring in useImportance of safety monitoring in useConfidence in vaccines, governments and public Confidence in vaccines, governments and public health systems will be on the line

“Those who cannot remember thepast are condemned to repeat it"

health systems will be on the line

Rapid Flu Vaccine Production

JAN FEB MAR APR MAY JUN JUL AUG SEP OCT NOV DEC

PREPARE SEED

MONOVALENT PRODUCTION

FILL/TEST

FIRST VACCINE TO PEOPLE!

IMMUNOGENICITY?

OUTBREAK

ACTIVE SAFETY/SAE DATA/HCD CONTINUED PHARMACOVIGILENCE

(Licensed vs. EUA)

ConclusionsConclusions

We have made progress to improve vaccine technology and We have made progress to improve vaccine technology and streamline regulatory pathways streamline regulatory pathways -- BUTBUT-- many issues still need many issues still need to be resolved to successfully deal with a Pandemic Flu crisisto be resolved to successfully deal with a Pandemic Flu crisisMany potential options exist and would be consideredMany potential options exist and would be consideredExpansion of capacity and use of facilities that have been Expansion of capacity and use of facilities that have been licensed for production of human pharmaceutical products, to licensed for production of human pharmaceutical products, to produce licensed products, is most straightforward approach to produce licensed products, is most straightforward approach to augment production in an emergencyaugment production in an emergencyAny product intended for large scale use, even in an Any product intended for large scale use, even in an emergency and if used as an unlicensed product, will need to emergency and if used as an unlicensed product, will need to have clinical data that support an assessment that benefits are have clinical data that support an assessment that benefits are likely to outweigh riskslikely to outweigh risks

ConclusionsConclusions

FDA regulations allow flexibility to consider the emergency FDA regulations allow flexibility to consider the emergency use of veterinary vaccine production facilities, but this would use of veterinary vaccine production facilities, but this would require a careful risk/benefit assessment of any product and require a careful risk/benefit assessment of any product and manufacturing facilities manufacturing facilities –– and is best accomplished before a and is best accomplished before a pandemicpandemicFDA and USDA have and will continue to engage in FDA and USDA have and will continue to engage in discussions to determine if any barriers exist, and if so, take discussions to determine if any barriers exist, and if so, take steps to address themsteps to address themContinue to work with other regulatory agencies and Continue to work with other regulatory agencies and manufacturers to facilitate Global Pandemic effortsmanufacturers to facilitate Global Pandemic efforts