Vaccines and related biological products advisory committee meeting
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Vaccines and Related Biological Products Advisory Committee Meeting. Influenza Vaccine, Recombinant Hemagglutinin FluBlok Protein Sciences Corporation Cynthia Nolletti, MD FDA/CBER/OVRR/DVRPA November 19, 2009. Presentation Outline. Product Summary Regulatory History Clinical Overview

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Vaccines and related biological products advisory committee meeting

Vaccines and Related Biological Products Advisory Committee Meeting

Influenza Vaccine, Recombinant HemagglutininFluBlokProtein Sciences Corporation

Cynthia Nolletti, MD

FDA/CBER/OVRR/DVRPA

November 19, 2009


Presentation outline

Presentation Outline

  • Product Summary

  • Regulatory History

  • Clinical Overview

  • Clinical Trials

    • PSC04

    • PSC06

    • PSC03

    • PSC01

  • Summary of Efficacy and Immunogenicity

  • Overview of Safety

  • Overall Conclusions

  • Questions for the Committee


Product summary

Product Summary

  • Product: trivalent recombinant hemagglutinin influenza vaccine consisting of three recombinant influenza hemagglutinin antigens derived from H1, H3, and B strains, inserted into a baculovirus vector, and expressed in Spodoptera frugiperda insect cells.

  • Proper name: Influenza Vaccine, Recombinant Hemagglutinin

  • Proprietary name: FluBlok

  • Proposed Indication: For active immunization of adults 18 years of age and older against influenza disease caused by influenza virus subtypes A and type B represented in the vaccine.

  • Dosage Form and Route of Administration: 135μg influenza HA antigen (45μg per influenza virus strain) per 0.5mL dose administered as a single dose intramuscularly.


Regulatory history

Regulatory History

  • October 23, 2004 – original IND filed

  • December 11, 2006 - Fast track granted

  • September 21, 2007 – Pre-BLA meeting

  • April 18, 2008 – Original BLA submission requesting accelerated approval.

  • August 29, 2008 – Complete Response letter issued.

  • April 28, 2009 – Complete Response submitted with additional clinical efficacy data. Traditional approval requested.


Clinical overview

Clinical Overview

  • Data from four clinical trials (one phase 2, three phase 3) submitted in support of approval of the 135μg dose

  • Two placebo-controlled and two active-controlled trials

  • Safety population: 3233 FluBlok recipients

    • 23% ≥ 50 years of age; 13% ≥ 65 years of age

  • Vaccine efficacy population: 2344 FluBlok recipients

    • 100% 18 to 49 years of age

  • Immunogenicity population: 1323 FluBlok recipients

    • 55% ≥ 50 years of age; 32% ≥ 65 years of age


Clinical trials overview

Clinical Trials Overview

*n=evaluable population for safety and clinical efficacy analyses

**135μg dose group

MDB = modified double-blind, person administering vaccine not blinded.


Clinical overview immunogenicity assessments

Clinical Overview: Immunogenicity Assessments

Immunogenicity endpoints were assessed using the hemagglutinin inhibition (HAI) assay and FDA criteria for acceptable immune responses.*

Although there is no established immune correlate of protection, the HI response may be an acceptable surrogate marker of activity that is reasonably likely to predict clinical benefit.

Previous studies suggest that HI titers of ≥ 1:40 correlate with protection against illness.

* Guidance for Industry: Clinical Data Needed to Support the Licensure of Seasonal Inactivated Influenza Vaccines (May 2007).

7


Clinical overview immunogenicity assessments1

Clinical Overview: Immunogenicity Assessments

The HAI assay and influenza viral cultures (nasal swab/throat swabs) were performed at a single central laboratory.

A validated assay using BEVS-derived* antigens was used to test sera from all treatment groups in the phase 3 studies. Egg-derived HA antigens were used in the phase 2 study.

*BEVS=baculovirus expression vector system

8


Clinical overview immune response endpoints

Clinical Overview: Immune Response Endpoints

  • Seroconversion rate (SCR): defined as the proportion of subjects with:

    • Pre-vaccination HI titer < 1:10 and a post-vaccination titer ≥ 1:40, or

    • Pre-vaccination HI titer ≥ 1:10 and a minimum 4-fold rise in post-vaccination titer.

  • Proportion of subjects achieving a post-vaccination HI titer ≥ 1:40

    • HI titers were drawn on Days 0 and 28 in all studies


Clinical overview fda immune response acceptance criteria

Clinical Overview FDA Immune Response Acceptance Criteria

  • For adults < 65 years of age:

    • The lower bound of the two-sided 95% CI (LB) for the SCR should meet or exceed 40%.

    • The LB for the proportion of subjects achieving a post-vaccination HI antibody titer ≥ 1:40 should meet or exceed 70%.

  • For adults ≥ 65 years of age:

    • LB for SCR should be ≥ 30%

    • LB for post-vaccination HI ≥ 1:40 should be ≥ 60%.


Clinical overview non inferiority endpoints and acceptance criteria

Clinical OverviewNon-inferiority Endpoints and Acceptance Criteria

  • GMT ratio of TIV to FluBlok 28 days post-vaccination for each vaccine strain

    • The upper bound of the 2-sided 95% CI (UB) on the GMT ratio should not exceed 1.5

  • The difference between the SCRs of TIV and FluBlok:

    (SCR TIV – SCR FluBlok)

    • The UB should not exceed 10%.


Clinical overview clinical endpoint assessments

Clinical OverviewClinical Endpoint Assessments

  • For the clinical efficacy endpoint, absolute vaccine efficacy (VE) relative to placebo was assessed in young healthy adults in studies PSC04 and PSC01.

    • Vaccine Efficacy (VE) = (1 – RR) x 100 = (1- Pv/Pp) x 100

      • RR = relative risk

      • Pv=proportion of FluBlok recipients and Pp=proportion of Placebo recipients who developed culture-confirmed ILI

  • For the active control studies PSC06 and PSC03, the Relative Efficacy (RE) (or % Relative Reduction) of FluBlok to Fluzone was calculated using descriptive statistics as:

    • RE = (1 – RR) x 100.


Overview clinical endpoint assessments ili

Overview: Clinical Endpoint Assessments - ILI

  • Influenza-like Illness (ILI) was assessed using a Flu Symptom scoring card. Subjects were to contact the clinic if they scored 2 or more points:

    • 1 point: fever ≥ 100ºF oral

    • 1 point: cough, sore throat, or runny nose/stuffy nose

    • 1 point: muscle or joint aches, headache,

      chills/sweats, tiredness/malaise

  • CDC-ILI was defined as fever of ≥100°F oral accompanied by cough and/or sore throat on the same day or on consecutive days.

  • ILI was monitored by active and passive surveillance for 6 months and/or until the end of the influenza season (EOIS) (whichever was longer) in all studies.


Study psc04

Study PSC04

Subjects 18 to 49 years of age


Study psc04 2007 2008

Study PSC04 (2007-2008)

  • Phase 3 placebo-controlled trial of safety and efficacy in healthy young adults 18 to 49 years of age

  • Primary Objectives

    • Safety: to determine safety relative to placebo

    • Efficacy: to determine efficacy relative to placebo

  • Secondary Objectives

    • Immunogenicity: to assess immune responses to FluBlok according to acceptance criteria


Psc04 18 49yr design

PSC04 (18-49yr): Design

  • Phase 3, prospective, randomized, double-blind, placebo-controlled

  • 4648 healthy adults age 18-49 years at 24 US sites

  • Randomized 1:1 FluBlok or placebo

  • Immunogenicity subset of 480 FluBlok recipients at 5 sites selected for immunogenicity analyses

  • Reactogenicity events collected through Day 7, Unsolicited AEs through Day 28, and SAEs through Day 180.


Psc04 18 49 yr efficacy endpoints

PSC04 (18-49 yr): Efficacy Endpoints

  • Primary Efficacy Endpoint:

    • The proportion of subjects in each treatment group with culture-confirmed CDC-ILI associated with isolation of an influenza virus antigenically resembling vaccine strains (“matched” strains)

  • Vaccine Efficacy (VE) = (1 – RR) x 100

  • PSC04 was powered to assess the LB of the two-sided 95% CI (LB) of VE around a point estimate of 70%.

  • Acceptance criteria: the LB of the 95% CI for VE of FluBlok relative to placebo should be ≥ 40%


Psc04 18 49 yr efficacy endpoints1

PSC04 (18-49 yr): Efficacy Endpoints

  • Secondary and Exploratory Efficacy Endpoints:

    • Proportion with culture-confirmed ILI (not necessarily CDC-ILI) due to matched strains.

    • Proportion with culture-confirmed ILI due to any (matched and mismatched) influenza virus strains.


Psc04 18 49 yr immunogenicity endpoints

PSC04 (18-49 yr): Immunogenicity Endpoints

  • Immunogenicity Endpoints:

    • Seroconversion rate for each vaccine strain

    • Proportion of subjects with a Day 28 post-vaccination HI titer ≥ 1:40 for each vaccine strain


Psc04 18 49 yr disposition of subjects

PSC04 (18-49 yr): Disposition of Subjects

*Does not include pregnancies

**Serology available for immunogenicity analysis. Placebo serologies run as post hoc analysis.


Psc04 18 49 yr efficacy results

PSC04 (18-49 yr): Efficacy Results

  • 646 swabs from 583 subjects obtained during the 180-day surveillance period.

  • 64 (2.7%) FluBlok and 114 (4.9%) placebo had culture-confirmed ILI.

  • 2007-2008 vaccine strains were poorly matched to circulating viral strains.

    • 170 of 178 total isolates antigenically mismatched

    • 111 of 119 type A isolates antigenically mismatched

    • 58 of the 59 B isolates mismatched; 1 not typed


Psc04 18 49 yr vaccine efficacy

PSC04 (18-49 yr): Vaccine Efficacy

22

*Includes one untyped B strain


Psc04 18 49 yr summary of vaccine efficacy

PSC04 (18-49 yr): Summary of Vaccine Efficacy

  • VE results for FluBlok against culture-confirmed ILI due to antigenically matched strains limited by small numbers of cases.

  • Point estimate of VE against culture-confirmed ILI for all strains regardless of antigenic match was 44.8%.

  • LB 95% CI of VE for type A strains was 24.7%, and for type B strains included zero.


Psc04 18 49 immunogenicity endpoints

PSC04 (18-49): Immunogenicity Endpoints

All 3 strains met both immunogenicity endpoints

Acceptance criteria: *LB 95% CI ≥ 40%; **LB 95% CI ≥ 70%


Study psc06

Study PSC06

Subjects 50 to <65 Years of Age


Study psc06 50 64 yr

Study PSC06 (50-64 yr)

  • Non-inferiority comparison of FluBlok to Fluzone in healthy adults 50 to 64 years of age.

  • Safety Objective:

    • to compare the safety and reactogenicity of FluBlok and Fluzone

  • Efficacy Objective:

    • to compare the relative efficacy of FluBlok and Fluzone in the prevention of culture-confirmed ILI

  • Immunogenicity Objective:

    • to compare the immunogenicity of FluBlok and Fluzone according to pre-specified non-inferiority criteria


Psc06 50 64 yr design

PSC06 (50-64 yr): Design

  • Phase 3, prospective, randomized, double-blind, active-controlled

  • 602 subjects at 5 sites in California and Hawaii

  • Randomized 1:1 FluBlok or Fluzone

  • Reactogenicity events collected through Day 7, Unsolicited AEs through Day 28, SAEs through Day 180


Psc06 50 64 yr efficacy endpoints

PSC06 (50-64 yr): Efficacy Endpoints

  • Proportion with culture-confirmed ILI due to matched strains

  • Proportion with culture-confirmed ILI regardless of antigenic match

  • Statistical analyses for the clinical endpoints were descriptive


Psc06 50 64yr non inferiority endpoints

PSC06 (50-64yr)Non-inferiority Endpoints

  • GMT ratio of Fluzone to FluBlok 28 days post-vaccination for each vaccine strain

    • The UB on the GMT ratio should not exceed 1.5

  • The difference between the SCRs of Fluzone and FluBlok: (SCR Fluzone – SCR FluBlok)

    • The UB should not exceed 10%


Psc06 50 64 yr efficacy results

PSC06 (50-64 yr): Efficacy Results

  • There were no antigenically matched isolates.

  • The total numbers of antigenically mismatched isolates was small in both groups: FluBlok =7 and Fluzone = 4.

  • Case numbers are too small and the confidence intervals are too wide to draw meaningful conclusions regarding the relative risk of influenza illness in recipients of FluBlok compared to Fluzone in healthy adults 50 to 64 years of age.

  • Because the clinical endpoint data in this age group was not adequate, the immunogenicity data provided an important surrogate marker of clinical benefit (next slide)…


Psc06 50 64 yr gmts and gmt ratio of fluzone to flublok at day 28

PSC06 (50-64 yr)GMTs and GMT Ratio of Fluzone to FluBlok at Day 28

**UB 95%CI ≤ 1.5

*based on Statistical Reviewer’s adjustments for pre-vaccination titer, prior vaccination history, and assay variables.


Psc06 50 64yr difference in seroconversion rates at day 28

PSC06 (50-64yr)Difference in Seroconversion Rates at Day 28

*Acceptance criteria: UB 95%CI ≤ 10%.


Psc06 50 64 yr immunogenicity results

PSC06 (50-64 yr): Immunogenicity Results

  • FluBlok met all 6 endpoints establishing non-inferiority to Fluzone.


Study psc03

Study PSC03

Subjects 65 years and older


Study psc03 2006 2007

Study PSC03 (2006-2007)

  • Non-inferiority comparison of FluBlok to Fluzone in adults 65 years and older

  • Safety Objective:

    • To compare the safety and reactogenicity of FluBlok and Fluzone

  • Efficacy Objective:

    • To compare the relative efficacy of FluBlok and Fluzone in the prevention of culture-confirmed ILI

  • Immunogenicity Objective:

    • To compare the immunogenicity of FluBlok and Fluzone


Psc03 65 yr design

PSC03 (≥ 65 yr): Design

  • Phase 3, prospective, randomized, double blind, active-controlled

  • 870 medically stable adults ≥ 65 years of age at 6 US study sites

  • Randomized 1:1 FluBlok or Fluzone

  • Reactogenicity events through Day 7, Unsolicited AEs through Day 28, and SAEs through Day 180


Psc03 65 yr endpoints

PSC03 (≥ 65 yr): Endpoints

  • Efficacy

    • Proportion of subjects in each vaccine group who experienced culture-confirmed CDC-ILI

    • Proportion who experienced any culture-confirmed medically attended acute respiratory illness

    • Descriptive statistics were used to calculate a Relative Efficacy of FluBlok to Fluzone:

      • RE = (1 – RR) x 100.


Psc03 65 yr non inferiority endpoints

PSC03 (≥ 65 yr): Non-inferiority Endpoints

  • GMT ratio of Fluzone to FluBlok

  • The difference in SCRs (Fluzone – FluBlok)


Psc03 65 yr clinical efficacy results

PSC03 (≥ 65 yr): Clinical Efficacy Results

  • Of 53 sets of cultures, only 3 were positive, 2 Fluzone and 1 FluBlok, all three for influenza Type A.

  • The case numbers are too small and the confidence intervals are too wide to draw meaningful conclusions from study PSC03 regarding the relative risk of influenza illness in recipients of FluBlok compared to Fluzone in adults 65 years of age and older.


Psc03 65 yr gmts and gmt ratios at day 28

PSC03 (≥ 65 yr): GMTs and GMT Ratios at Day 28

**UB 95% CI on GMT ratio ≤ 1.5

*Based on Statistical Reviewer’s adjustments for pre-vaccination titers and HI assay variables


Psc03 65 yr difference in seroconversion rates at day 28

PSC03 (≥ 65 yr)Difference in Seroconversion Rates at Day 28

*UB 95% CI for (SCR TIV –SCR FluBlok) should be ≤ 10%


Psc03 65 yr immunogenicity endpoint results

PSC03 (≥ 65 yr)Immunogenicity Endpoint Results

  • FluBlok met 5 of the 6 primary endpoint criteria for demonstrating non-inferiority to Fluzone.

  • H1 and H3 antigens met both non-inferiority endpoints.

  • B strain demonstrated non-inferiority to Fluzone by the GMT ratio, but not by SCR criteria.


Study psc01

Study PSC01

Subjects 18 to 49 Years of Age


Study psc01 2004 2005

Study PSC01 (2004-2005)

  • Phase 2 dose-finding safety, immunogenicity and efficacy study in healthy adults 18 to 49 years of age

  • Safety Objective:

    • To determine safety relative to placebo

  • Immunogenicity Objective:

    • To compare the immunogenicity of two dose levels of FluBlok, 75µg versus 135µg total HA antigen*

  • Efficacy Objective:

    • To determine clinical efficacy in the prevention culture-confirmed ILI.

*FluBlok 75µg = 15µg H1, 45µg H3, 15µg B strain

FluBlok 135μg = 45μg per strain


Psc01 18 49 yr efficacy endpoint

PSC01 (18-49 yr): Efficacy Endpoint

  • Clinical Efficacy

    • Proportion with culture-confirmed ILI

  • The study was not powered to test formal null hypotheses. Descriptive statistics were used to detect trends between the treatment groups.


Psc01 18 49 yr vaccine efficacy results

PSC01 (18-49 yr): Vaccine Efficacy Results

*Blue shade: For these parameters both FluBlok dose group results (n=151 + 150) are included because both doses contained 45μg of the predominant H3N2 strain.


Psc01 18 49 yr vaccine efficacy

PSC01 (18-49 yr): Vaccine Efficacy

  • Antigenically dissimilar H3N2 virus predominated

  • VE of the 135μg dose was 87.3% (LB 5.5%) against all culture-positive ILI and against all strains regardless of match.

  • Because H3N2 predominated and because both the 75 and 135µg dose groups contained 45µg of H3 antigen, if all cases from subjects who received the 75μg dose are included in the analysis, VE decreased to 68.2% (LB -10.1%).

  • The estimates of VE in study PSC01 suggest a favorable trend. However, this study was not powered to test a formal null hypothesis of vaccine efficacy and it is limited by the overall small sample size and wide confidence intervals.


Clinical efficacy and immunogenicity populations across studies flublok 135 g

Clinical Efficacy and Immunogenicity Populations across Studies – FluBlok 135μg


Summary vaccine efficacy across studies

Summary: Vaccine Efficacy across Studies

  • PCS04 (18-49 yr)

    • Despite antigenic mismatch, overall VE against culture-confirmed illness due to any strain was 44.8% (LB 24.4%).

    • Point estimates against all type A and all type B influenza were 49.0% and 37.2% respectively.

    • Failed to meet primary endpoint against antigenically matched strains because mismatched circulating virus predominated.

  • PCS01 (18-49 yr)

    • Antigenic mismatch predominated. Descriptive statistics demonstrated a favorable trend towards VE: 87.3% (LB 5.5%) against all culture-confirmed ILI.

  • PCS03 and PSC06 (≥ 50 yr)

    • Unable to assess RE because of very small numbers of cases.


Efficacy conclusions

Efficacy Conclusions

In healthy adults (18 to 49 years), the VE of FluBlok against culture-confirmed influenza due to antigenically mismatched strains was 44.8% (LB 24.4%).

The efficacy data is driven by study PSC04 (adults 18 to 49 years of age) where the sample size and the attack rate were adequate to assess absolute vaccine efficacy (VE) against placebo.

50


Immune response and non inferiority endpoints across clinical studies flublok 135 g

Immune Response and Non-inferiority Endpoints across Clinical Studies - FluBlok 135μg

  • H1 and H3 strains met both immune response endpoints in adults 18-49 years of age (PSC04 and PSC01).

  • H1 and H3 strains met both criteria for non-inferiority to Fluzone in older adults in the two studies that evaluated non-inferiority endpoints, PSC03 and PSC06.

  • The B strain met both immune response endpoints in the largest and pivotal study, PSC04, of young healthy adults.

  • B strain met both criteria for non-inferiority to Fluzone in study PSC06, adults 50-64 years of age.

  • B strain met the GMT ratio endpoint, but failed the seroconversion endpoint for non-inferiority to Fluzone in study PSC03, adults ≥ 65 years of age.


Immunogenicity conclusions

Immunogenicity Conclusions

  • FluBlok is immunogenic in young adults 18-49 years. The FluBlok H1 and H3 antigens also elicited a robust immune response that was non-inferior to Fluzone in adults 50 years of age and older.

  • The B antigen failed to demonstrate non-inferiority in elderly adults ≥ 65 years of age. Similar weak responses to the B strain have been noted in studies of older adults using currently licensed TIVs.


Safety

Safety


Overview of safety across trials

Overview of Safety Across Trials

  • The safety database for FluBlok 135μg consisted of 3233 subjects 18 to over 65 years of age.

  • 23% of subjects were ≥ 50 years of age; 13% were ≥ 65 years of age

  • Females and Caucasians represented the majority of subjects.


Safety deaths

Safety: Deaths

There were a total of six deaths across the four studies, 2 occurring in young previously healthy adults (PSC04) and 4 occurring in subjects > 65 years of age (PSC03). The deaths were balanced, 3 in FluBlok recipients, 3 in control groups, and none appeared related to the study vaccines.

*assessed by investigator and Reviewer as not related because of lack of

temporal relationship and/or biologic plausibility


Safety serious adverse events through day 180

Safety: Serious Adverse Events through Day 180

N= # subjects who experienced an SAE, counted only once regardless of number of events per individual

E= # events overall including more than one SAE per individual

*Causality assessed by site investigator


Sae s assessed as possibly related or related to flublok

SAE’s Assessed as Possibly Related or Related to FluBlok

  • PSC04 Subject 05-03221 - Pleuropericarditis

    • 47 year-old male, history of hypertension, onset within 11 days of vaccination with FluBlok

    • Extensive evaluation: no specific etiology

    • Discharge diagnosis: possible viral pleuropericarditis

    • Investigator assessment: possibly related

  • PSC06 Subject 01-0036 - Vasovagal syncope

    • 57 year old male, onset within 15 minutes of phlebotomy and receipt of FluBlok

    • Report not suggestive of an anaphylactic or hypersensitivity reaction

    • Event compatible with vasovagal syncope associated with phlebotomy and/or intramuscular injection

    • Investigator assessment: related


Summary of saes by meddra system organ class

Summary of SAEs by MedDRA* System Organ Class

Medical Dictionary for Regulatory Activities

FB=FluBlok; PBO=placebo; E = # of events

Continued


Summary of saes by meddra system organ class cont

Summary of SAEs by MedDRA System Organ Class (cont)

59


Safety hypersensitivity events

Safety: Hypersensitivity Events

  • As part of the safety review, the data was evaluated for hypersensitivity events across studies.

  • Electronic datasets from each of the four studies (FluBlok n=3233) were searched for hypersensitivity-type reactions using MedDRA preferred terms.* The Applicant was asked to provide case narratives, case report forms, and consulting physicians’ notes for all hypersensitivity-type events.

    * Preferred terms included immune system disorders, hypersensitivity, drug hypersensitivity, adverse drug reaction, allergy, anaphylaxis, hives, urticaria, serum sickness, vasculitis, swelling, angioedema, allergic asthma, anemia, lymphadenopathy, thrombocytopenia, immune thrombocytopenia, arthralgia, myalgia, synovitis, rash, and rash pruritic.


Safety results of search for hypersensitivity type events

Safety Results of Search for Hypersensitivity-type Events

  • Rash:

    • Rates lower in FluBlok group compared to Fluzone.

    • None in the FluBlok recipients were serious or severe.

    • Majority appeared unrelated to FluBlok.


Hypersensitivity type events continued

Hypersensitivity-Type Events (continued)

Of the remaining hypersensitivity-type events in FluBlok recipients, there were 2 events across studies that were either serious or severe and may have been related to FluBlok:

one case of pleuropericarditis (already discussed);

one case of swelling of the lips and tongue.

62


Hypersensitivity type events continued1

PSC04 Subject 19731 – Hypersensitivity

22 y.o. female history of seasonal allergic rhinitis, exercise-induced symptoms (bronchiolar constriction, facial edema, edema of extremities, rash, itchiness, and swelling of the tongue), mild asthma, and headaches.

Abrupt onset of swollen lips and tongue 10 hours and 20 minutes following vaccination.

Self-medicated with Claritin (loratidine)10mg and Benadryl 25mg. Symptoms resolved by Study Day 2.

Investigator assessed event as moderate and possibly related to the study vaccine.

Hypersensitivity-Type Events (continued)

63


Hypersensitivity type events continued2

Hypersensitivity-Type Events: (Continued)

  • The safety database did not reveal other hypersensitivity-type safety signals.

  • The data did not reveal large imbalances in these events between treatment groups.


Safety reactogenicity events across trials

Safety: Reactogenicity Events across Trials

  • Most frequent events in FluBlok subjects: local pain, headache, fatigue and myalgia. Rates similar to Fluzone:


Safety unsolicited adverse events

Safety: Unsolicited Adverse Events

  • Unsolicited AEs:

    • Rates were similar between FluBlok and Control groups.

    • Most frequent across studies: headache (0.3-8.4%) and symptoms of respiratory infection (0-5.9%)*

    • Most assessed as not related to study vaccines; most mild to moderate.

  • No other unusual trends, patterns or safety signals were observed.

  • No reports of Guillain Barre Syndrome or other autoimmune type events.

  • Frequency of Unsolicited AEs similar to licensed TIVs.

  • Analysis of individuals over 65 years of age did not reveal safety issues unique to this age group.

*Symptoms of URI: cough, pharyngolaryngeal pain, nasal congestion, URI, nasopharyngitis


Safety conclusions

Safety Conclusions

  • The safety database for FluBlok 135μg consisted of 3233 subjects 18 to over 65 years of age.

  • Deaths were few (6 total), balanced, and appeared unrelated to the study vaccines.

  • The vast majority of SAEs occurred in subjects older than 65 years of age, and were assessed as unrelated to the study vaccines.

  • Two SAEs in FluBlok recipients were related or possibly related to the vaccine: vasovagal syncope and pleuropericarditis.

  • There was no large imbalance of hypersensitivity events.

  • No other unusual trends, patterns or safety signals were observed.

  • Overall, the type and frequency of adverse events experienced by FluBlok subjects was similar to those reported for other trivalent influenza vaccines.


Overall conclusions

Overall Conclusions

  • FluBlok demonstrated an absolute vaccine efficacy of 44.8% (LB 24.4%) against antigenically mismatched influenza strains in healthy adults 18 to 49 years of age.

  • FluBlok elicited robust immune responses to H1 and H3 and somewhat weaker responses to B antigen in older adults.

  • Safety data did not reveal unexpected trends or safety signals.

  • The type and frequency of adverse events experienced by FluBlok subjects was similar to those reported for other TIVs.


Questions for the committee

Questions for the Committee

  • Do the available clinical data support effectiveness of FluBlok in the prevention of influenza disease caused by influenza subtypes A and type B included in the vaccine in adults:

    • 18 to 49 years of age;

    • 50 to 64 years of age;

    • 65 years and older?


Questions for the committee1

Questions for the Committee

  • Do the available safety data support the safety of FluBlok in adults 18 years and older?


Questions for the committee2

Questions for the Committee

  • Please comment on what additional studies, if any, should be requested post-licensure.


Backup slides

Backup Slides


Clinical overview race and ethnicity across studies

Clinical Overview: Race and Ethnicity across Studies

*July 2007 census

**Hispanic origin is considered an ethnicity, not a race; Hispanics may be any race.


Demographic characteristics across studies evaluable population for immunogenicity

Demographic Characteristics across StudiesEvaluable Population for Immunogenicity

*n=Evaluable Population **This variable was not evaluated in the post hoc placebo group analyses

The majority of subjects across studies were Caucasian. The demographic characteristics of the total Evaluable Population for Clinical Efficacy and of the Safety Population across studies were almost identical to those presented above.


Psc04 populations

PSC04: Populations

  • Safety Analysis – Safety Population

    • All randomized subjects who received Study Vaccine categorized according to actual treatment received

  • Efficacy Analysis – Evaluable Population

    • Immunogenicity – all subjects who met eligibility criteria, were randomized, had no major protocol violations, and had HI titers taken at Day 0 and Day 28, categorized based on actual treatment received.

    • Clinical Efficacy – all subjects who met eligibility criteria, were randomized, had no major protocol violations, and completed at least 50% of follow-up telephone contacts, including the end of influenza season (EOIS) call, categorized based on actual treatment received.


Psc04 18 49 yr vaccine efficacy1

PSC04 (18-49 yr): Vaccine Efficacy

76

*Includes one untyped B strain


Psc06 results disposition of subjects

PSC06 – ResultsDisposition of Subjects

*Complete Study Report


Psc06 other immune response endpoints

PSC06: Other Immune Response Endpoints

Proportion of subjects with Post-vaccination HI titer ≥ 1:40

*Immune response acceptance criteria: LB 95% CI should be ≥ 70%


Psc06 other immune response endpoints1

PSC06: Other Immune Response Endpoints

Seroconversion Rate

*Acceptance criteria: LB ≥ 40%.


Psc03 disposition of subjects

PSC03: Disposition of Subjects


Psc03 analysis populations

PSC03: Analysis Populations

  • Safety Population: all randomized subjects who received any dose of study medication

  • Evaluable Population

    • for Immunogenicity: all randomized subjects who received the correct dose of vaccine and had titers taken at baseline and at Day 28

    • for Relative Risk (Relative Efficacy): All subjects who received the correct dose of vaccine.


Psc03 immune response endpoints

PSC03: Immune Response Endpoints

*Acceptance criteria = LB 95% CI for %4-fold rise must be ≥ 30%.

**Acceptance criteria = LB 95% CI for % HI ≥1:40 must be ≥ 60%.


Psc03 other immune response endpoints proportion with day 28 hi titer 1 40

PSC03: Other Immune Response EndpointsProportion with Day 28 HI Titer ≥ 1:40

*Acceptance criteria: LB 95% CI for % HI ≥1:40 should be ≥ 60%


Psc03 seroconversion 4 fold rise in hi titer

PSC03: Seroconversion/4-fold Rise in HI Titer

*Acceptance criteria = LB 95% CI for %4-fold rise must be ≥ 30%.


Psc01 statistical considerations

PSC01: Statistical Considerations

  • Sample Size

    • The study was not powered to test formal null hypotheses, but descriptive statistics were used to detect trends between the treatment groups.

  • Seroconversion: A sample size of 450 subjects, 150 per treatment group was selected to ensure that a 15% or greater difference in the seroconversion rate between treatment groups would be detected with an α=0.05 and 80% power. This assumed that 60-80% of subjects would have a 4-fold rise in HI titer.

  • Clinical Efficacy: The Applicant calculated that, for a placebo group attack rate of 5%, a sample size of 150 subjects per arm would detect a minimum difference of 13.4% in cases of culture-confirmed ILI between treatment groups with 80% power.


Psc01 disposition of subjects

PSC01: Disposition of Subjects


Psc01 18 49 yr immunogenicity results

PSC01 (18-49 yr): Immunogenicity Results

  • The 135μg dose was more immunogenic than the 75μg dose and was selected for further clinical development.

  • The HAI assay for this study was validated, but used a different dilution series (LOD 1:4 instead of 1:10) than for the other clinical trials of FluBlok. More stringent acceptance criteria using HI titer thresholds of ≥ 1:64 were applied to the SCR and % HI ≥ 1:40 endpoints.

  • The 135μg dose met 5 of the 6 immune response endpoints. 57.1% (LB 95% CI) of subjects met the criteria for a post-vaccination HI titer of ≥ 1:64. If the post-vaccination threshold was changed to ≥ 1:32, 76.4% (LB) of subjects met the endpoint.


Psc01 18 49 yr immunogenicity results1

PSC01 (18-49 yr): Immunogenicity Results

*LB 95% CI for SCR must be at least 40%

**LB 95% CI for % HI ≥ 1:64 must be at least 70%


Considerations in the evaluation of vaccine efficacy in the presence of antigenic mismatch

Considerations in the Evaluation of Vaccine Efficacy in the Presence of Antigenic Mismatch

  • VE is influenced by the degree of antigenic match between vaccine strains and circulating virus. Low attack rates and small sample sizes may also contribute to unreliable or variable estimates of efficacy.

  • Estimates of efficacy in young healthy adults have ranged from 70% to 90% when the vaccine and circulating viruses are well-matched. These estimates are limited by the relative lack of randomized, placebo-controlled trials (RPCT).

  • Studies conducted during seasons where the vaccine and circulating strain are poorly matched have demonstrated lower efficacy.

  • Because variability in attack rates and/or antigenic drift can make assessments of VE over a single season difficult, multiple seasons may provide a more accurate estimate of VE.


Considerations in the evaluation of vaccine efficacy in the presence of antigenic mismatch cont

Considerations in the Evaluation of Vaccine Efficacy in the Presence of Antigenic Mismatch (cont)

  • To put the efficacy data from PSC04 in perspective, we examined results from a series of 3 annual RPCTs conducted by Monto A, Ohmit, SE, and others at the University of Michigan.

  • These studies estimated the absolute and relative efficacies of licensed TIV and LAIV in healthy adults 18-49 years of age.

  • Three influenza seasons were studied: 2004-2005; 2005-2006; and 2007-2008; results are summarized in the next slide.


Vaccines and related biological products advisory committee meeting

Randomized Placebo-Controlled Trials of Vaccine EfficacyOhmit SE, Monto A, et al, University of Michigan

1Ohmit SE, et al. N Eng J Med 2006;355:2513-22.

2Ohmit SE, et al. J Infect Dis 2008; 198:312-7.

3Monto A, et al. N Eng J Med 2009; 361:1260-7.


Estimates of vaccine efficacy in the literature where antigenic characterization is available

Estimates of Vaccine Efficacy in the Literature where Antigenic Characterization is Available

  • Although it is difficult to make direct comparisons because of differences in study design and methodology, the following table, adapted from Jackson L, et al, JID 2009, presents results of some recently published studies of VE against culture-confirmed influenza with antigenic characterization:


Vaccine efficacy and antigenic characterization from recently published literature

Vaccine Efficacy and Antigenic Characterization from Recently Published Literature

Adapted from Jackson LA. J Infect Dis 2009; 199:155-158

*point estimates, by strain if known; red type indicates matched strains

**VE based on both culture and real-time PCR-confirmed cases;

RPCT=randomized placebo-control trial


Vaccine efficacy and antigenic characterization from recently published literature cont

Vaccine Efficacy and Antigenic Characterization from Recently Published Literature (cont)

Adapted from Jackson LA. J Infect Dis 2009; 199:155-158

*point estimates, by strain if known; red type indicates matched strains


Immune response and non inferiority endpoints across studies flublok 135 g

Immune Response and Non-inferiority Endpoints across Studies – FluBlok 135μg

*PSC01 used a higher HI threshold of ≥ 1:64


Immune response and non inferiority endpoints across studies flublok 135 g1

Immune Response and Non-inferiority Endpoints across Studies – FluBlok 135μg

*PSC01 used a higher HI threshold of ≥ 1:64


Psc04 deaths

PSC04: Deaths

  • Death from Pulmonary Embolism - Subject 02568: a 47 y.o. female vaccinated on September 9, 2007. No concomitant vaccinations. On Jan 1, 2008 (94 days post-vaccination), the subject was hospitalized and died from a PE.

    • Applicant reported that details were not available because husband did not have authority to sign for reports.

    • Investigator assessed event as not related.


Hypersensitivity type events continued3

Hypersensitivity-Type Events (continued)

  • Of the remaining hypersensitivity-type events in FluBlok recipients:

    • 2 were either serious or severe and may have been caused by FluBlok;

    • 2 were mild and/or probably unrelated to FluBlok;

    • 2 were suggestive of seasonal allergies or infection-related rhinitis, were not temporally related to vaccination, appeared unrelated.

    • 1 was a dermatitis due to topical use of neomycin


Hypersensitivity type events continued4

Hypersensitivity-Type Events (continued)

  • PCS04 Subject 12074 – Hypersensitivity/facial swelling

    • 35 y.o. female

    • Grade 1 injection site pain on Day 0, then no complaints.

    • Day 16: dizziness, nausea, pruritis and facial swelling.

    • Private MD evaluation on Day 16: red puffy eyes and puffy upper lip, otherwise unremarkable.

    • Labs normal except for mildly elevated ESR 34 (nl 0-20).

    • Resolved without specific treatment.

    • Investigator assessed as not related.

  • PSC06 Subject 0266 – Urticaria

    • 52 yo female experienced corneal abrasion, sinus pain and hives four days post-vaccination.

    • Hives assessed as non-serious, mild in intensity and possibly related to the study vaccine.


Overview of safety pregnancy outcomes

Overview of Safety: Pregnancy Outcomes

*FluBlok: hyperemesis, pulmonary embolism, staph infection, miscarriage;

Fluzone: kidney stone, appendicitis, hypertension, ectopic pregnancy, miscarriage


Safety rash psc04

Safety: Rash – PSC04

  • Rash: 4 FluBlok and 1 Placebo subject in PSC04 reported rash. One FluBlok subject had a moderate intensity rash assessed as possibly related to the study vaccine, but that resolved without sequelae. The remainder were mild, non-serious, and assessed as not related to study vaccines.

#12475: 34 year old female vaccinated with FluBlok on Sept 19, 2007. PMH included seasonal allergies and allergy to “mycins”. On Days 2-4 she experienced left leg and back bruising, felt not related to the vaccine, and rash on the face, neck, chest and shoulder. The rash was described as moderate, required no treatment, and resolved without sequelae. The rash was assessed as possibly related to the study vaccine because of the temporal relationship between vaccination and onset.


Safety rash in flublok recipients cont

Safety: Rash in FluBlok Recipients (cont)

  • PSC06: Urticaria: Subject #0266 was vaccinated with FluBlok on Oct 23, 2007. Four days post-vaccination, the subject reported hives. Assessed as non-serious, mild in intensity and possibly related to the study vaccine. Resolved without sequelae after treatment with medication on October 27, 2007.

  • PSC03: Five total, none serious or severe. Two FluBlok subjects had rashes that were ongoing at the time of the interim analysis (Day 28). Subject #0572 experienced a facial rash that was considered mild, non-serious, and not related to the vaccine. FluBlok Subject #1086 had eczema, also non-serious, mild, and assessed as not related to the vaccine. Remaining 3: ingrown toenail, sebaceous cyst, and blisters from topical antibiotic.

  • PSC01: Rash occurred in two subjects, both in the FluBlok 75µg group. Subject 2401 experienced rash in the left axillary area 22 days post-vaccination. Subject 2441 experienced a rash in the left antecubital area 4 days post-vaccination. Neither was considered serious, both were assessed as mild and unrelated to the study vaccine, and both resolved without sequelae.


Safety discontinuations due to aes psc04

Safety: Discontinuations Due to AEs – PSC04*

*PSC01 and PSC06: No discontinuations due to AEs.

PSC03: One Fluzone recipient discontinued due to cerebral hemorrhage.


Safety questionable case of bell s palsy

Safety: Questionable Case of Bell’s Palsy

  • Possible Bell’s Palsy: Subject 17759 was a 35 y.o. female with a history of prior episodes of Bell’s Palsy

  • In 1988, during pregnancy, and in March 2007: characterized by numbness in her cheek. Treated with a steroid injection in March 2007.

  • Subject experienced similar prodromal symptoms of recurrence (watery eyes) one day prior to vaccination, and was symptomatic (numbness of the cheek)within one hour of vaccination on Day 0.

  • Symptoms resolved without treatment or sequelae by Day 3, and did not recur by the end of the study.

  • Event described as mild, not serious, not related to the study vaccine.


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