Vaccines and Related Biological Products Advisory Committee Meeting

November 14, 2012

Influenza A (H5N1) Virus Monovalent Influenza A (H5N1) Virus Monovalent Vaccine, AdjuvantedVaccine, Adjuvanted

(Q-Pan H5N1 Vaccine) (Q-Pan H5N1 Vaccine) Manufactured by GlaxoSmithKlineManufactured by GlaxoSmithKline

Carmen M. Collazo-Custodio, Ph.D.

Office of Vaccines Research and Review/CBER/FDA

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Overview of Today’s AgendaOverview of Today’s Agenda Introduction

• Jesse L. Goodman, M.D., M.P.H. Background

• Carmen M. Collazo-Custodio, Ph.D. (FDA, DHHS) Vaccine Adjuvants & Mode of Action for GSK’s AS03-Adjuvanted Influenza A

(H5N1) Virus Monovalent Vaccine• Dr. Hana Golding, Ph.D. (FDA, DHHS)

USG Programs and Goals for Antigen-Sparing Pandemic Influenza Vaccines • Robin Robinson, Ph.D. (BARDA, DHHS)

Pandemic Vaccine Effectiveness: Experience During the H1N1 Pandemic• Joseph Bresee, M.D. (CDC, DHHS)

GSK Presentation• Donna Boyce• Bruce Innis, M.D.• Felix Arellano, M.D.

FDA Presentation of Clinical Data• Andrea James, M.D. (FDA, DHHS)

Committee Discussion and Vote

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Background OutlineBackground Outline Currently licensed seasonal and pandemic

influenza virus vaccines

Description: Q-Pan H5N1 Vaccine [Influenza A (H5N1) Virus Monovalent Vaccine, Adjuvanted]

Background:February 2012 VRBPAC: Licensure of Pandemic

Influenza Vaccines: Demonstration of Effectiveness

Pathway to licensure of Q-Pan H5N1 Vaccine [Influenza A (H5N1) Virus Monovalent Vaccine, Adjuvanted]

Questions to the Committee

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US-Licensed Seasonal and Pandemic US-Licensed Seasonal and Pandemic Influenza Virus VaccinesInfluenza Virus Vaccines

Seasonal Influenza Vaccines (Inactivated)• Afluria (CSL)

• Agriflu (Novartis)

• Fluarix (GSK)

• FluLaval (IDB-GSK)

• Fluvirin (Novartis)

• Fluzone (Sanofi Pasteur)

• Fluzone High-Dose (Sanofi Pasteur)

• Fluzone Intradermal (Sanofi Pasteur)

Seasonal Influenza Vaccine (live attenuated, intranasal)• FluMist (MedImmune)

Monovalent Pandemic Influenza Vaccines • H5N1 Influenza Virus Vaccine

(Inactivated) • Sanofi Pasteur

• H1N1 Influenza A (H1N1) 2009 Monovalent Vaccines (inactivated, IM)

• CSL

• IDB-GSK

• Novartis

• Sanofi Pasteur

• H1N1: Influenza A (H1N1) 2009 Monovalent Vaccine Live, Intranasal

• MedImmune

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H5N1 Influenza Virus Vaccine (Strain A/Vietnam/1203/2004)

Discussed by VRBPAC in February 2007

Manufactured by Sanofi Pasteur, Inc. using the same egg-based manufacturing process as the seasonal influenza virus vaccine, Fluzone

Vaccine is included in the US Strategic National Stockpile

Safety and immunogenicity data generated supported the:

• dose of antigen [90 g hemagglutinin (HA)/1 mL dose]

• dosing regimen (2 doses, ~ 28 days apart)

Approved in April 2007 for use in persons 18-64 years of age

Effectiveness was inferred from Fluzone, the seasonal vaccine (“traditional” approval pathway)

US-Licensed Pandemic Influenza Virus VaccineUS-Licensed Pandemic Influenza Virus Vaccine

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Seasonal Influenza Virus Vaccines

US-licensed Unadjuvanted

• FluLaval®1

• Fluarix®2

Pandemic Influenza Virus Vaccines

Not licensed in the US AS03-Adjuvanted

• Pumarix™ (Q-Pan H5N1)1

• Arepanrix™ (Q-Pan H1N1)1

• Prepandrix™ (D-Pan H5N1)2

• Pandemrix™ (D-Pan H1N1)2

1.1. Manufactured in Quebec, Canada, according to Manufactured in Quebec, Canada, according to the FluLaval manufacturing processthe FluLaval manufacturing process

2.2. Manufactured in Dresden, Germany, according Manufactured in Dresden, Germany, according to the Fluarix manufacturing processto the Fluarix manufacturing process

Portfolio of GSK’s Influenza Virus VaccinesPortfolio of GSK’s Influenza Virus Vaccines

GSK’s Pandemic Influenza Virus GSK’s Pandemic Influenza Virus Vaccines Vaccines

AS03-Adjuvanted Not licensed in the US

• Pumarix™ (Q-Pan H5N1)• Arepanrix™ (Q-Pan H1N1)• Prepandrix™ (D-Pan H5N1)• Pandemrix™ (D-Pan H1N1)

Post-marketing experience: Arepanrix and Pandemrix were widely used in the 2009 mass vaccination campaigns conducted during the H1N1 influenza virus pandemic. 7

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Background OutlineBackground Outline Currently licensed seasonal and pandemic

influenza vaccines

Description: Q-Pan H5N1 Vaccine [Description: Q-Pan H5N1 Vaccine [Influenza A Influenza A (H5N1) Virus Monovalent Vaccine, Adjuvanted](H5N1) Virus Monovalent Vaccine, Adjuvanted]

Background:February 2012 VRBPAC: Licensure of Pandemic

Influenza Vaccines: Demonstration of Effectiveness

Pathway to licensure of Q-Pan H5N1 (Influenza A (H5N1) Virus Monovalent Vaccine, Adjuvanted)

Questions to the Committee

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• US government contracted GSK to develop and submit for licensure a candidate H5N1 influenza virus vaccine with antigen-sparing potential

• Vaccine is to be included in the US Strategic National Stockpile

• GSK submitted a Biologics License Application (BLA) in February 2012

Q-Pan H5N1 VaccineQ-Pan H5N1 VaccineInfluenza A (H5N1) Virus Monovalent Influenza A (H5N1) Virus Monovalent

Vaccine, AdjuvantedVaccine, Adjuvanted

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Q-Pan H5N1 VaccineQ-Pan H5N1 Vaccine Applicant: ID Biomedical Corporation of

Quebec (doing business as GlaxoSmithKline Biologicals)

Description: Vaccine consists of inactivated, split A/H5N1 influenza virus HA antigen and AS03 oil-in-water emulsion adjuvant• The H5N1 antigen is manufactured in Quebec,

Canada according to the FluLaval manufacturing process

• Hence, referred to as Q-Pan or Q-Pan H5N1 (Q-Pan for pandemic antigen manufactured in Quebec)

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Each 0.5 mL vaccine dose contains: 3.75 mcg hemagglutinin (HA) of A/Indonesia/5/2005 5 mcg thimerosal preservative AS03 oil-in-water emulsion adjuvant:

• 11.86 mg D,L--tocopherol (vitamin E)• 10.69 mg squalene• 4.86 mg polysorbate 80

Q-Pan H5N1Q-Pan H5N1 Vaccine VaccineDescription

Q-Pan H5N1 VaccineQ-Pan H5N1 VaccineDescription (continued)

Supplied as two separate multi-dose vials H5N1 antigen and AS03 adjuvant are

combined prior to administration• Yielding a multi-dose presentation of the

vaccine• Resulting in ten 0.5 mL doses

Vaccine is for intramuscular administration Vaccine is administered as a 2-dose

schedule given ~ 21 days apart 12

Q-Pan H5N1 VaccineQ-Pan H5N1 Vaccine

Proposed indication: Q-Pan H5N1 is a vaccine indicated for active immunization for the prevention of influenza disease in persons 18 years of age and older at increased risk of exposure to the influenza A virus H5N1 subtype contained in the vaccine.

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Background OutlineBackground Outline Currently licensed seasonal and pandemic

influenza vaccines

Description: Q-Pan H5N1 Vaccine [Influenza A (H5N1) Virus Monovalent Vaccine, Adjuvanted]

Background:Background:February 2012 VRBPAC: Licensure of Pandemic February 2012 VRBPAC: Licensure of Pandemic

Influenza Vaccines: Demonstration of EffectivenessInfluenza Vaccines: Demonstration of Effectiveness

Pathway to licensure of Q-Pan H5N1 Vaccine [Influenza A (H5N1) Virus Monovalent Vaccine, Adjuvanted]

Questions to the Committee

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February 2012 VRBPAC: Licensure February 2012 VRBPAC: Licensure of Pandemic Influenza Vaccinesof Pandemic Influenza Vaccines

Approaches to demonstrating the effectiveness of a pandemic influenza vaccine manufactured by the same process as a US-licensed seasonal influenza vaccine

Seasonal influenza vaccine may have been licensed via two different regulatory pathways:• “Traditional” Approval pathway• Accelerated Approval regulations

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Adjuvanted Influenza Virus Vaccine, H5N1:Adjuvanted Influenza Virus Vaccine, H5N1:Seasonal vaccine Seasonal vaccine licensed via the “Traditional” Approval pathway

US-licensed seasonal influenza

vaccine unadjuvanted

“Prototype”pandemic vaccine

adjuvanted

Licensure approach:““Traditional” ApprovalTraditional” Approval

safety immunogenicity• HA dose• adjuvant content• dosing regimen

effectiveness

““Traditional” Traditional” ApprovalApproval

safetyimmunogenicityefficacy

strain change supplement

pandemicH5N1 vaccine

Pandemic vaccine adjuvanted

Effectiveness inferred from efficacy of the seasonal

Pandemic periodPre-pandemic period

e.g., H5N1

Slide 16: This diagram illustrates the scenario where the seasonal vaccine has been licensed via the traditional approval pathway. To obtain traditional approval of the seasonal vaccine, the manufacturer must have had demonstrated the safety and the immunogenicity of the vaccine, as well as the efficacy of the seasonal vaccine through clinical endpoint efficacy studies. To license a “prototype’ adjuvanted pandemic vaccine during the pre-pandemic period, a manufacturer must conduct safety studies and generate immunogenicity data to define the hemagglutinin dose, the adjuvant content, and the dosing regimen. In addition, to obtain traditional approval of this prototype pandemic vaccine during the pre-pandemic period, the manufacturer would have to demonstrate the effectiveness of the product. This is where it becomes challenging, because in the pre-pandemic period there is no circulating pandemic strain, so clinical endpoint efficacy studies with that vaccine candidate are not feasible. During the February VRBPAC, FDA proposed to infer effectiveness of the “prototype” strain from the efficacy data accrued with the seasonal vaccine. In this scenario, the “prototype” pandemic vaccine is also licensed via the traditional approval pathway. Licensure in the pre-pandemic period would permit use of a strain-change supplement to approve a vaccine well matched to the circulating influenza strain in the event of a pandemic (as illustrated in the green box).

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Adjuvanted Influenza Virus Vaccine, H5N1:Adjuvanted Influenza Virus Vaccine, H5N1: Seasonal vaccine licensed via the Accelerated Approval regulationsSeasonal vaccine licensed via the Accelerated Approval regulations

Accelerated Approval may be granted for certain biological products for serious or life-threatening illnesses (21 CFR 601.41 Subpart E)

Approval of a pandemic influenza virus vaccine (e.g., H5N1) via the Accelerated Approval regulations would be based on:• Safety data accrued with the “prototype” pandemic vaccine

• Immunogenicity data: approval “…on the basis of adequate and well-controlled clinical trials establishing that the product has an effect on a surrogate endpoint …reasonably likely…to predict clinical benefit…” [i.e., hemagglutination inhibition (HI) antibody assay to evaluate immune response]

• Approval “...subject to the requirement that the applicant study the biological product further to verify and describe its clinical benefit…” (post-marketing confirmatory study or studies)

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Adjuvanted Influenza Virus Vaccine, H5N1: Seasonal vaccine licensed via the Accelerated Approval regulationsSeasonal vaccine licensed via the Accelerated Approval regulations

US-licensed seasonal influenza

vaccine unadjuvanted

Accelerated Accelerated ApprovalApproval

e.g., H5N1

Licensure of “prototype”pandemic vaccine

adjuvanted

Licensure approach:Accelerated ApprovalAccelerated Approval

safety & immunogenicity

Pre-pandemic period

Option AOption A: Effectiveness verified when efficacy of the seasonal is confirmed

““Traditional” ApprovalTraditional” Approval

effectiveness

OR

Option BOption B: Effectiveness verified using observational effectiveness data with non-US-licensed adjuvanted H1N1 vaccine

Efficacy not verified

Pandemic: strain change

supplement

Slide 19: In this scenario, the seasonal vaccine has been licensed under the accelerated approval regulations – and, therefore, efficacy (i.e., clinical benefit, meaning prevention of influenza illness) of the seasonal vaccine has not been demonstrated or verified through clinical endpoint efficacy studies. In this setting, the “prototype” adjuvanted H5N1 vaccine would also be licensed under the accelerated approval regulations during the pre-pandemic period. This means that the manufacturer would have to demonstrate the safety, as well as the immunogenicity of this vaccine to support dose and dose regimen by conducting clinical studies. During the February VRBPAC, FDA outlined two approaches to demonstrate effectiveness of the “prototype” pandemic vaccine. The first approach, represented as option A in this diagram, is that effectiveness would be verified when the efficacy of the vaccine is confirmed. FDA has also accepted another approach, shown as option B in this diagram, which is that effectiveness of the pandemic vaccine is verified using observational effectiveness data with a non-U.S.-licensed adjuvanted H1N1 vaccine. Here, effectiveness is inferred from these observational data.

Under either of these approaches, options A or B, licensure in the pre-pandemic period allows the use of a strain-change supplement to approve a vaccine well matched to the circulating pandemic strain in the event of a pandemic.

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The Role of Post-Licensure Studies for The Role of Post-Licensure Studies for H5N1 Vaccines During a PandemicH5N1 Vaccines During a Pandemic

During a pandemic, post-licensure studies could be used to collect additional effectiveness and safety data for pandemic vaccines• The applicant is expected to work with government

agencies on plans to collect additional effectiveness and safety information when the pandemic vaccine is used.Note that this is considered a post-marketing

commitment (not a requirement under the Accelerated Approval regulations).

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Background OutlineBackground Outline

Currently licensed seasonal and pandemic influenza vaccines

Description: Q-Pan H5N1 Vaccine [Influenza A (H5N1) Virus Monovalent Vaccine, Adjuvanted]

Background:Background:February 2012 VRBPAC: Licensure of Pandemic

Influenza Vaccines: Demonstration of EffectivenessPathway to licensure of Q-Pan H5N1 Vaccine Pathway to licensure of Q-Pan H5N1 Vaccine

[[Influenza A (H5N1) Virus Monovalent Vaccine, Influenza A (H5N1) Virus Monovalent Vaccine, Adjuvanted]Adjuvanted]

Questions to the Committee

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Q-Pan H5N1 VaccineQ-Pan H5N1 VaccineFluLavalFluLaval licensed via the Accelerated Approval regulationslicensed via the Accelerated Approval regulations

Q-Pan H5N1 is manufactured by the same process as FluLaval (unadjuvanted seasonal vaccine)

Licensure of FluLaval was based on the review of safety and immunogenicity data via the Accelerated Approval regulations

Efficacy of FluLaval in preventing influenza illness has not yet been demonstrated; however,• Results from a controlled study to verify the clinical

benefit of FluLaval were recently submitted to FDA by GSK i.e., study Q-QIV-006, confirmatory study for “traditional” approval

of FluLaval

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Q-Pan H5N1 Vaccine BLAQ-Pan H5N1 Vaccine BLA

Within the context of the regulatory status of FluLaval, GSK submitted a BLA for Q-Pan H5N1 on February 22, 2012

The clinical package included:• Safety and immunogenicity data accrued with the Q-Pan

H5N1 vaccine• Additional supportive safety and immunogenicity data• Effectiveness data from an observational study

conducted during the 2009 influenza pandemic with Arepanrix (GSK’s AS03-adjuvanted H1N1 pandemic influenza vaccine manufactured by the same process as FluLaval ) (Option BOption B)

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Q-Pan H5N1 Vaccine BLAQ-Pan H5N1 Vaccine BLAApproaches for Granting “Traditional” Approval of the Approaches for Granting “Traditional” Approval of the

Q-Pan H5N1 VaccineQ-Pan H5N1 Vaccine After review, CBER does not consider the

Arepanrix (Q-Pan H1N1) effectiveness study sufficient for “traditional” approval of Q-Pan H5N1 (Option BOption B).

Therefore, GSK proposes to confirm the clinical benefit of Q-Pan H5N1 using efficacy data generated with the seasonal influenza vaccine made according to the same manufacturing process (Option AOption A).

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Accelerated Approval

Pathway to Licensure of Q-Pan H5N1 VaccinePathway to Licensure of Q-Pan H5N1 Vaccine Verify clinical benefit with efficacy data from seasonalVerify clinical benefit with efficacy data from seasonal

FluLavalFluLaval Q-Pan H5N1Q-Pan H5N1

Licensure approach:Accelerated Approval

safetysafety

immunogenicityimmunogenicity

Pre-pandemic periodPre-pandemic period

Efficacy data under review

“Traditional” Approval

“Traditional” Approval

Option AOption A: When efficacy of FluLaval is confirmed, effectiveness of Q-Pan H5N1 is verified

Option A:Option A: • Discussed at February VRBPAC• Approach agreed by CBER and GSK

Pandemic: strain change

supplement

Slide 26: To illustrate this approach, since FluLaval is licensed under the accelerated approval regulations and the efficacy data is under review by FDA, the “prototype” pandemic vaccine (Q-Pan H5N1), if licensed, would also be licensed via the accelerated approval regulations during the pre-pandemic period. This means that GSK would have to demonstrate the safety, as well as the immunogenicity of Q-Pan H5N1 to support dose and dose regimen by conducting clinical studies during the pre-pandemic period. GSK is then proposing that when efficacy of FluLaval is confirmed, effectiveness of Q-Pan H5N1 would be verified. Once this is accomplished, FluLaval and Q-Pan H5N1 would be licensed via the “traditional” approval pathway. Note that this option was discussed at the February VRBPAC and it was agreed by CBER and GSK in previous discussions. As previously discussed, licensure of the “prototype” pandemic vaccine in the pre-pandemic period allows the use of a strain-change supplement to approve a vaccine well matched to the circulating pandemic strain in the event of a pandemic.

The pathway described here for licensure of Q-Pan H5N1 occurs during the pre-pandemic period. What happens during then in the event of a pandemic? (See slide 28)

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Post-Licensure Plans During an H5N1 Post-Licensure Plans During an H5N1 Influenza PandemicInfluenza Pandemic

GSK has committed to work with government agencies on plans to collect additional effectiveness and safety information when the Q-Pan H5N1 vaccine is used.

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Summary: Approach to Grant “Traditional” Summary: Approach to Grant “Traditional” Approval of the Q-Pan H5N1 VaccineApproval of the Q-Pan H5N1 Vaccine

FDA has agreed to Option AOption A, that is, confirming the clinical benefit of Q-Pan H5N1 with data derived from the clinical endpoint efficacy study conducted with the seasonal influenza vaccine (FluLaval).

FDA views Option A as scientifically supportable and consistent with previous regulatory actions.

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Confirmatory Studies for Q-Pan H5N1 Vaccine Confirmatory Studies for Q-Pan H5N1 Vaccine During a PandemicDuring a Pandemic

Another approach (not discussed at February VRBPAC) would be for GSK to conduct an effectiveness study (or studies) during an H5N1 influenza virus pandemic to verify the clinical benefit of Q-Pan H5N1

Under the Accelerated Approval regulations:• GSK would be required to carry out such

studies with due diligence• Studies would have to be adequate and well-

controlled

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SummarySummary VRBPAC is being convened to review and discuss

presentations of safety and immunogenicity data derived from studies conducted with Q-Pan H5N1.

The committee will be asked to vote on whether the available data are adequate to support the safety and immunogenicity of Q-Pan H5N1 for use in adults at increased risk of exposure or during a pandemic.

The committee will be asked to discuss approaches to confirm the effectiveness of Q-Pan H5N1 for “traditional” approval.

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Background OutlineBackground Outline

Currently licensed seasonal and pandemic influenza vaccines

Background:February 2012 VRBPAC: Licensure of Pandemic

Influenza Vaccines: Demonstration of Effectiveness

Pathway to licensure of Q-Pan H5N1 Vaccine [Influenza A (H5N1) Virus Monovalent Vaccine, Adjuvanted]

Description: Q-Pan H5N1 Vaccine [Influenza A (H5N1) Virus Monovalent Vaccine, Adjuvanted]

Questions to the CommitteeQuestions to the Committee

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Questions to the Committee Questions to the Committee

1. Do the immunogenicity data support licensure of the Q-Pan H5N1 vaccine for use in adults at increased risk of exposure or during a pandemic?

Please vote yes or no.

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Questions to the Committee Questions to the Committee

2. Do the safety data support licensure of the Q-Pan H5N1 vaccine for use in adults at increased risk of exposure or during a pandemic?

Please vote yes or no.

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Discussion ItemDiscussion ItemPlease discuss the following two approaches to confirm the effectiveness of Q-Pan H5N1 for “traditional” approval.

1. To confirm the clinical benefit of Q-Pan H5N1 with efficacy data generated with a US-licensed seasonal influenza virus vaccine made according to the same manufacturing process.

2. To confirm the clinical benefit of Q-Pan H5N1 by conducting an effectiveness study (or studies) during an H5N1 influenza virus pandemic.

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Thank you!

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Overview of Today’s AgendaOverview of Today’s Agenda Introduction

• Jesse L. Goodman, M.D., M.P.H. Background

• Carmen M. Collazo-Custodio, Ph.D. Vaccine Adjuvants & Mode of Action for GSK’s AS03-Adjuvanted Influenza A

(H5N1) Virus Monovalent Vaccine• Dr. Hana Golding, Ph.D.

USG Programs and Goals for Antigen-Sparing Pandemic Influenza Vaccines • Robin Robinson, Ph.D.

Pandemic Vaccine Effectiveness: Experience During the H1N1 Pandemic• Joseph Bresee, M.D.

GSK Presentation• Donna Boyce• Bruce Innis, M.D.• Felix Arellano, M.D.

FDA Presentation of Clinical Data• Andrea James, M.D.

Committee Discussion