# Presentation: 827682

## Vaccines and Related Biological Products Advisory Committee Presentation on Sanofi Pasteur’s H5N1 Vaccine

- Andrea N. James, M.D.
- Senior Medical Officer
- Division of Vaccines and Related Product Applications

## Presentation Outline

- Summary of the Product
- FUG01 Study Description
- FUG01 Immunogenicity Results
- FUG01 Safety Results
- BLA Summary
- Limitations of the Data
- Questions to the Committee

- FDA VRBPAC Meeting

## Summary of the Product

- BLA submission date:  October 17, 2006
- Product: H5N1 Influenza Virus Vaccine, A/Vietnam/1203/2004 (clade 1)
- Proposed Dosage:  90 μg
- Proposed Administration:   Two 1mL IM injections administered 28 days apart.

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## Summary of Product (cont)

- Sanofi’s Proposed Indication: H5N1 Influenza Virus Vaccine, A/Vietnam/1203/2004 (clade 1) 90μg/mL is an influenza viral vaccine indicated for:
- Active immunization against influenza disease caused by  H5N1 A/Vietnam/1203/2004 (clade 1) influenza virus.
- Primary vaccination of healthy adults 18 through 64 years of age.

- FDA VRBPAC Meeting

## FUG01 Trial Design and Population Description

**Notes:**
Study FUG01, is the single clinical study that was submitted in support of this application.

##  FUG01 Study Design

- FUG01
- Phase I/II randomized, double blind, two-stage, placebo-controlled, dose ranging study
- Eligible subjects: healthy 18 – 64 years of age
- Stratified by age (< or _>_ 40 yrs) and prior seasonal influenza vaccine (2004 – 2005 season)
- Randomized 1:2:2:2:2 to 1 of 5 doses
- Saline placebo, 7.5 μg, 15 μg, 45 μg or 90 μg
- Placebo/vaccine administration: two 1mL intramuscular injections 28 days apart.

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**Notes:**
FUG01 is a Phase I/II randomized, double blind, two-stage, placebo-controlled, dose ranging study.

The study enrolled a total of 452 subjects.  Subjects were eligible if they were healthy and between the ages of 18 and 64 years (extremes included).  Subjects were stratified by age and prior seasonal influenza vaccine receipt and then randomized in a 1:2:2:2:2  fashion to 1 of 5 doses either saline Placebo, 7.5 μg, 15 μg, 45 μg or 90 μg.
Subjects then received their randomly assigned dose as two intramuscular injections administered 28 days apart.

## FUG01:  Study Design

- Study Objectives
- To determine the dose-related safety of subvirion inactivated H5N1 vaccine in healthy adults.
- 2) To determine the dose-related immunogenicity of subvirion inactivated H5N1 vaccine in healthy adults approximately 1 month following receipt of 2 doses of vaccine.
- 3) To provide information for the selection of the best dose levels for further studies.

- FDA VRBPAC Meeting

## FUG01:  Study Design

- HAI Immunogenicity Endpoint Analyses
- 4-fold or greater increases in serum HAI antibody titers 28 days after receipt of each dose, and 6 months after receipt of the second dose of vaccine.
- _>_ 1:40 serum HAI antibody titers 28 days after receipt of each dose, and 6 months after receipt of the second dose of vaccine.

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## FUG01:  Study Description

- Exploratory study
- Not statistically powered to provide estimates of immunogenicity at any specific dose.
- Not statistically powered to detect rare safety events
- Results provide trends

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**Notes:**
FUG01 was designed as an exploratory study, so all of the results I’m about to present need to be received with the following information in the forefront of your mind
This study is not hypothesis driven and therefore is not designed to produce statistically significant results, only trends.

Additionally the sample size is small with 452 subjects in all and 91 subjects in the per protocol immunogenicity population for to marketed dose, 90 mcg  and 103 subjects in the safety population for the to be marketed dose. 

## FUG01 Subject Demographics and Baseline Characteristics

- Subjects enrolled = 452
- Majority of subjects were
- Caucasian 80.8%
- Females 53.5%
- Mean age of 40.5 years (range: 18.1 – 64.9 years)
- Majority of subjects (58.4%)  had not received the 2004-2005 seasonal influenza vaccine
- 3.3% of all subjects had detectable H5 antibody at baseline

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**Notes:**
With that background I will move onto the study results

In terms of subject demographics and baseline characteristics...

## FUG01 Immunogenicity Results

**Notes:**
Now to present the immunogenicity results

## FUG01:  Percent of Per Protocol Subjects with 4-Fold HAI Titer Rise

| 4-Fold Rise in HAI titer
%
 | Placebo
N=42
 | 90 μg
N=91
 |
| --- | --- | --- |
| 
28 Days post Vaccination 1
95% CI |  
0
(0.0;8.4) | 
23.1%
(14.9;33.1) |
| 
28 Days post Vaccination 2
95% CI | 
0
(0.0;8.4)
 | 
45.1%
(34.6;55.8) |
| 
6 Months post Vaccination 2
95% CI |  
2.4%
(0.1;12.9) |  
17.6%
(10.4;27.0) |

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**Notes:**
On this slide we are looking at a tabular presentation of the first endpoint of percent of subjects who achieved a 4 fold rise in HAI titer.  In a moment I will show this data in graph form.  However you can see in this table that the 90 mcg group with 91 subjects in the per protocol population had approximately a 23% response rate 28 days after the first vaccine and a 45% response rate 28 days after the second vaccination with waning of this response rate by month 6 post vaccination 2.

## FUG01:  Percent of Subjects with 4-Fold HAI Titer Rise

- FDA VRBPAC Meeting

**Notes:**
This is a graphical presentation of what you just saw in the table.

I’ll take a moment to orient you to the slide.  On the x-axis is time in days and on the y-axis is percent of responders. The blue diamonds represent the placebo arm and the red squares represent the to be marketed 90 mcg dose arm with their respective 95% confidence interval bars. There are 4 distinct time points plotted for each study arm:  baseline, 28 days post vaccination 1, 28 days post vaccination  2 and 6 months post vaccination 2.  Please note that the dose groups are slightly separated in time on the graph, but this serparation is for graph clarity only.  All subjects were evaluated at the same study time points. The purplish hatch mark represents the 40% response rate threshold that the FDA recommends the lower bound of the 95% CI l be at or beyond for proportion of subjects with a 4 fold rise in HAI titer.  

You can see in this graph that the 90 mcg group is trending toward meeting this criteria 28 days after the second vaccination however it falls shy of the lower bound threshold by about 5%, which may be at least partially due to the small study sample size.

Currently in the FDA’s Draft Guidance for Industry on Clinical Data Needed to Support the Licensure of Pandemic Influenza Vaccineswe request that immunogenicity data for adults < 65 years of age meet certain criteria and those criteria are that the ...

## FUG01 Dose Response :  Percent of Subjects with 4-Fold HAI Titer Rise

- FDA VRBPAC Meeting

**Notes:**
This is a slide showing all 5 study arms and their respective percent point estimates at each scheduled time pointVery quickly, I’ve put up this slide to show you two things:  1.  at each of the four vaccine doses there is an immune response. And 2. the higher the vaccine dose the higher the response rate  2.  that there does appear to be a dose-dependent immune response.  On this graph you again have time in days on the x axis and % response on the y-axis.  You can see with increasing doses there appears to be a dose-dependent increase in the percentage of subjects who had a 4-fold rise in HAI titer.  

## FUG01: Percent of Subjects with HAI Titers > 1:40

| HAI Titer > 1:40
% | Placebo
N=42
 | 90 μg
N=91
 |
| --- | --- | --- |
| 
Baseline
95% CI | 
0
(0.0;3.8) | 
1.0%
(0.0;6.0) |
| 
28 Days post Vaccination 1
95% CI | 
2.4%
(0.1;12.6) |  
24.2%
(15.8;34.3) |
| 
28 Days post Vaccination 2
95% CI |  
2.4%
(0.1;12.6) | 
46.0%
(35.6;56.9) |
| 
6 Months post Vaccination 2
95% CI | 
4.8%
(0.6;16.5) | 
18.7%
(17.3;28.2) |

- FDA VRBPAC Meeting

**Notes:**
On this slide we are looking at a tabular presentation of the second endpoint of proportion of subjects who achieved an HAI titer of >= 1:40.  Again, in a moment I will show this data in graph form.  The numbers are very similar to the numbers seen for 4 fold rise.  You can see in this table that the 90 mcg group had approximately a 24% response rate 28 days after the first vaccine and a 46% response rate 28 days after the second vaccination with waning of this response rate by month 6 post vaccination 2.

## FUG01: Percent of Subjects with HAI Titers > 1:40

- FDA VRBPAC Meeting

**Notes:**
The graph is also very similar to the one I just showed you for 4-fold rise.  In this graph we see the proportion of subject who had HAI titers >= 1:40. I’ll again orient you to the slide.  On the x-axis is time in days and on the y-axis is percent response. The blue diamonds represent the placebo arm and the red squares represent the to be marketed 90 mcg dose arm with their respective 95% confidence interval bars. There are 4 distinct time points plotted for each study arm:  baseline, 28 days post vaccination 1, 28 days post vaccination  2 and 6 months post vaccination 2.  Again the dose groups are slightly separated in time for graph clarity only.  The purplish hatch mark represents the 70% response rate threshold that the FDA requests the lower bound of the 95% CI l be at or beyond for proportion of subjects with >=  1:40 HAI titer.  

You can see in this graph that the 90 mcg group is trending upward at the two 28 day post vaccination time point however it falls well short of the lower bound threshold of the 70% response rate.

## Additional Analyses

- Gender
- Race/Ethnicity
- Age and Prior Influenza Strata

**Notes:**
Additional analyses of select subject populations revealed some intriguing results

## PP Gender Subgroup Analysis:  Percent 4-Fold HAI Rise

| 
90 μg | Males
N = 41 | Females
N = 50 |
| --- | --- | --- |
| 
% Responders | 
46% | 
56% |

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## PP Race/Ethnicity Subgroup Analysis:  Percent 4-Fold HAI Rise

| 
90 ug | Caucasian 

N = 76 | Black

N = 9 | Asian

N = 6 | Hispanic

N = 11 |
| --- | --- | --- | --- | --- |
| 
% 
Responders | 

51.3% | 

55.6% | 

50% | 

81.8% |

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## Stratified Populations:  4-Fold Rise in HAI Titer

| 90 μg Group | Age < 40 years
N = 48 | Age > 40 years
N = 43 |
| --- | --- | --- |
| No 2004/05 Influenza Vaccine 
N = 52 | 75%
(24/32) | 35%
(7/20) |
| Received 2004/05 Influenza Vaccine 
N = 39 | 37.5%
(6/16) | 43.5%
(10/23) |

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**Notes:**
I performed additional analyses on the prespecified strata namely age and prior seasonal influenza vaccine.  This graph looks at all subjects in the per protocol population who experienced a 4-Fold Rise in HAI titer at any measurable time point during the study.  Right away you see that the younger subjects who did not receive the prior year seasonal influenza vaccine appeared to have a better immune response than their age-matched counterparts who did receive the 2004-2005 seasonal influenza vaccine and overall better than the older subjects.  Even in the > 40 year group, subjects who did not receive prior influenza vaccination appeared to respond slightly better than subjects who did receive the prior influenza vaccination.

The literature is somewhat controversial on this issue but there is evidence that suggests that prior influenza vaccination can negatively impact the immune response to an antigenically distant epidemic strain. 

## Immunogencity Summary

- This H5N1 vaccine appears to have a dose related immune response.
- 90 μg dose appears to have a better response rate
- ~45% of subjects responding after two doses of vaccine.
- Immunogenicity observed in this study is less than what is usually seen in seasonal influenza vaccine studies.
- The impact of gender, ethnicity and prior seasonal vaccination on H5 immunogenicity is unclear and may warrant further exploration.

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## H5N1 Safety Results 

## FUG01 Safety Assessments

- Frequency and incidence of
- Immediate reactions
- 15 – 30 minutes post vaccinations.
- Solicited local and systemic reactions
- Day 0 through Day 7 post vaccinations
- Unsolicited AEs and SAEs
- Study Day 0 through Day 56

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**Notes:**
Safety was assessed by frequency and incidence of immediate reactions (15 – 30 minutes post vaccination), solicited local injection site  and systemic reactions (Day 0 – Day 7 post vaccinations 1 and 2), unsolicitecd AEs and SAEs in each dose group (Day 0 through Day 56).

Safety population database includes 451 subjects

## Safety Data Background

- Solicited injection site (local) AEs included:
- Pain
- Tenderness
- Redness
- Swelling

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## Safety Data Background (cont)

- Solicited systemic AEs included:
- Feverishness
- Malaise
- Body aches (exclusive of the injection site)
- Nausea
- Headache

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## SAEs

- Four SAEs: none considered vaccine related
- One death (45 μg arm)
- 52 y.o. male with h/o chronic alcoholism
- Death secondary to sequelae of chronic alcoholism
- Three other SAES
- Breast cancer (placebo arm)
- Menorrhagia (15 μg arm)
- Cerebrovascular accident (90 μg arm)

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## Local Reactogenicity Events

|  | Placebo
N=48 | 7.5μg
N=101 | 15 μg
N=101
 | 45 μg
N=98
 | 90 μg
N=103 |
| --- | --- | --- | --- | --- | --- |
| % Subjects with > 1 
 Injection Site AE(s) | 45.8% | 59.4% | 68.3% | 78.6% | 84.5% |
| % Subjects with Moderate (Gr 2) Injection Site AEs | 0 | 3.0% | 5.0% | 7.1% | 13.9% |
| % Subjects with Severe (Gr 3) Injection Site AEs | 0 | 0 | 0 | 0 | 0  |
| # of Injection Site AEs | 89 | 237 | 266 | 424 | 537  |
| Pain | 22.5% | 21.9% | 33.5% | 35.1% | 36.1% |
| Tenderness | 21.3% | 29.1% | 34.2% | 35.4% | 35.2% |
| Erythema/Redness | 34.8% | 35.9% | 23.3% | 22.4% | 18.2% |
| Induration/Swelling | 21.3% | 13.1% | 9.0% | 7.1% | 10.4% |

- FDA VRBPAC Meeting

**Notes:**
If we look at local reactogenicity events, there was a dose-dependent frequency of local reactogenicity events with the 90 mcg dose group having approx 85% of subjects with injection site reactions, the majority of these events being pain and tenderness, and approx 14% of subjects having  injection site reactions of moderate severity.  

## Systemic Reactogenicity Events

|  | Placebo
N=48 | 7.5μg
N=101 | 15 μg
N=101
 | 45 μg
N=98
 | 90 μg
N=103
 |
| --- | --- | --- | --- | --- | --- |
| % Subjects with > 1 
Systemic AE(s)	 | 58.3% | 39.6% | 47.5% | 35.7%  | 47.6% |
| % Subjects with Moderate (Gr 2) Systemic AEs | 20.8% | 14.9% | 20.8% | 6.1% | 11.7% |
| % Subject with Severe (Gr 3) Systemic AEs | 0 | 1.0% | 2.0% | 0 | 1.0% |
| # of Systemic AEs | 125 | 207 | 349 | 109 | 171 |
| Headache | 36% | 33.8% | 30.7% | 40.4% | 38.0% |
| Malaise | 34.4% | 27.5% | 28.0% | 28.4% | 29.8% |
| Body aches | 22.4% | 21.3% | 23.5% | 19.3% | 17.0% |
| Nausea  | 3.2% | 9.7% | 12.0% | 6.4% | 8.8% |
| Feverishness | 4.0% | 7.7% | 5.7% | 5.5% | 6.4% |

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**Notes:**
When we look at systemic events were a lot less common than injections site reactions and systemic events did not appear to be dose related.

## Safety Summary

- Dose dependent increase in frequency of local reactogenicity events
- Pain and tenderness more common in the 90 μg group
- No other apparent safety signals

- FDA VRBPAC Meeting

**Notes:**
So in summary for safety results 

## BLA Summary

- BLA for H5N1 Influenza Virus Vaccine, A/Vietnam/1203/2004 (clade 1)
-  90 μg
- Two 1mL IM injections administered 28 days apart.
- Immunogenicity observed in study FUG01 is less than what is usually seen in seasonal vaccine studies.
- ~45% of subjects responding after two doses of vaccine
- No apparent safety issues

- FDA VRBPAC Meeting

**Notes:**
So to summarize, Sanofi has submitted an application seeking licensure for their biologic product, H5N1 influenza virus vaccine, A/Vietnam/1203/2004 (clade 1) at a recommended dose of 90 mcg to be administered as two 1 mL intramuscular injections 28 days apart.

Based on the data submitted with the BLA it appears as though the 90 mcg dose is trending towards being the more immunogenic dose however it is still poorly immunogenic using current FDA standards of assessing immunogenicity with approximately 45% of subjects responding after two doses of vaccine.

## Limitations of the Data

- Clinical database is small
- Not statistically powered to detect rare adverse events.
- Not statistically powered to produce statistically significant results.
- Results provide trends only.
- Unknown clinical efficacy of this vaccine.
- Unknown correlate of protection against H5.
- Unknown impact of gender, ethnicity, and prior seasonal influenza vaccination.

- FDA VRBPAC Meeting

**Notes:**
Unfortunately there are many limitations of the data contained in this BLA and therefore our ability to make firm conclusions about the data are limited

First the clinical database is small

## Questions to the Committee

## Sanofi’s Proposed Indication

- H5N1 Influenza Virus Vaccine, A/Vietnam/1203/2004 (clade 1) 90μg/mL is an influenza viral vaccine indicated for:
- Active immunization against influenza disease caused by  H5N1 A/Vietnam/1203/2004 (clade 1) influenza virus.
- Primary vaccination of healthy adults 18 through 64 years of age.

- FDA VRBPAC Meeting

## 	1.   Are the data sufficient to support the effectiveness of this product for use during a pandemic or in situations of potential high risk exposure. 

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## 2. Are the data sufficient to support the safety of this product for use during a pandemic or in situations of potential high risk exposure. 

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## 3.  Please comment on studies to collect additional information about the effectiveness and safety following this vaccine’s use. 

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## Acknowledgement Slide

- Tammy Massie, PhD
- Melisse Baylor, MD
- Antonia Gerber, MD
- Joseph Toerner, MD, MPH
- Douglas Pratt, MD
- David Menschik, MD
- Therese Cvetkovich, MD

- Zhiping Ye, MD, PhD
- Carmen Collazo, PhD
- Rakesh Pandey, PhD
- Marion Gruber, PhD
- Mark Goldberger, MD, MPH
- Florence Houn, MD
- Norman Baylor, PhD

- FDA VRBPAC Meeting