Influenza A (H5N1) Virus Monovalent Vaccine, Adjuvanted (Q-Pan H5N1 Vaccine) Manufactured by GlaxoSmithKline Vaccines and Related Biological Products Advisory.

Presentation on theme: "Influenza A (H5N1) Virus Monovalent Vaccine, Adjuvanted (Q-Pan H5N1 Vaccine) Manufactured by GlaxoSmithKline Vaccines and Related Biological Products Advisory."— Presentation transcript:

1 Influenza A (H5N1) Virus Monovalent Vaccine, Adjuvanted (Q-Pan H5N1 Vaccine) Manufactured by GlaxoSmithKline Vaccines and Related Biological Products Advisory Committee Meeting November 14, 2012 Influenza A (H5N1) Virus Monovalent Vaccine, Adjuvanted (Q-Pan H5N1 Vaccine) Manufactured by GlaxoSmithKline Carmen M. Collazo-Custodio, Ph.D. Office of Vaccines Research and Review/CBER/FDA 1

2 2 Overview 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

3 3 Background 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

4 4 US-Licensed Seasonal and Pandemic Influenza 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

5 5 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 Vaccine

6 6  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.Manufactured in Quebec, Canada, according to the FluLaval manufacturing process 2.Manufactured in Dresden, Germany, according to the Fluarix manufacturing process Portfolio of GSK’s Influenza Virus Vaccines

7 GSK’s Pandemic Influenza Virus 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

8 8 Background Outline  Currently licensed seasonal and pandemic influenza 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 (Influenza A (H5N1) Virus Monovalent Vaccine, Adjuvanted)  Questions to the Committee

9 9 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 Vaccine Influenza A (H5N1) Virus Monovalent Vaccine, Adjuvanted

10 10 Q-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)

11 11 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 H5N1 Vaccine Q-Pan H5N1 Vaccine Description

12 Q-Pan H5N1 Vaccine Q-Pan H5N1 Vaccine Description (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

13 Q-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. 13

14 14 Background Outline  Currently licensed seasonal and pandemic influenza 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

15 15 February 2012 VRBPAC: Licensure of 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

16 16 Adjuvanted Influenza Virus Vaccine, H5N1: Seasonal vaccine Adjuvanted Influenza Virus Vaccine, H5N1: Seasonal vaccine licensed via the “Traditional” Approval pathway US-licensed seasonal influenza vaccine   unadjuvanted “Prototype” pandemic vaccine   adjuvanted Licensure approach: “Traditional” Approval   safety   immunogenicity HA dose adjuvant content dosing regimen   effectiveness “Traditional” Approval   safety   immunogenicity   efficacy strain change supplement pandemic H5N1 vaccine Pandemic vaccine   adjuvanted Effectiveness inferred from efficacy of the seasonal Pandemic periodPre-pandemic period e.g., H5N1

17 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).

18 18 Adjuvanted Influenza Virus Vaccine, H5N1: Seasonal 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)

19 19 Seasonal vaccine licensed via the Accelerated Approval regulations Adjuvanted Influenza Virus Vaccine, H5N1: Seasonal vaccine licensed via the Accelerated Approval regulations US-licensed seasonal influenza vaccine   unadjuvanted Accelerated Approval e.g., H5N1 Licensure of “prototype” pandemic vaccine   adjuvanted Licensure approach: Accelerated Approval   safety & immunogenicity Pre-pandemic period Option A Option A: Effectiveness verified when efficacy of the seasonal is confirmed “Traditional” Approval   effectiveness OR Option B Option B: Effectiveness verified using observational effectiveness data with non- US-licensed adjuvanted H1N1 vaccine Efficacy not verified Pandemic: strain change supplement

20 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.

21 21 The Role of Post-Licensure Studies for H5N1 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).

22 22 Background Outline  Currently licensed seasonal and pandemic influenza 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

23 23 Q-Pan H5N1 Vaccine FluLavallicensed via the Accelerated Approval regulations Q-Pan H5N1 Vaccine FluLaval licensed 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

24 24 Q-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 Option BEffectiveness 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 B)

25 25 Q-Pan H5N1 Vaccine BLA Approaches for Granting “Traditional” Approval of the Q-Pan H5N1 Vaccine Option B  After review, CBER does not consider the Arepanrix (Q-Pan H1N1) effectiveness study sufficient for “traditional” approval of Q-Pan H5N1 (Option B). Option A  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 A).

26 26 Accelerated Approval Pathway to Licensure of Q-Pan H5N1 Vaccine Verify clinical benefit with efficacy data from seasonal FluLaval Q-Pan H5N1 Licensure approach: Accelerated Approval  safety  immunogenicity Pre-pandemic period Efficacy data under review “Traditional” Approval Option A Option A: When efficacy of FluLaval is confirmed, effectiveness of Q-Pan H5N1 is verified Option A: Discussed at February VRBPAC Approach agreed by CBER and GSK Pandemic: strain change supplement

27 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)

28 28 Post-Licensure Plans During an H5N1 Influenza 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.

29 29 Summary: Approach to Grant “Traditional” Approval of the Q-Pan H5N1 Vaccine Option A  FDA has agreed to Option 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.

30 30 Confirmatory Studies for Q-Pan H5N1 Vaccine During 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

31 31 Summary  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.

32 32 Background 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 Committee

33 33 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.

34 34 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.

35 35 Discussion Item Please 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.

36 36 Thank you!

37 37 Overview 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