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FluMist ® age extension Five years & younger May 16, 2007. FDA presentation. Efficacy: Therese Cvetkovich, M.D. Medical Officer CBER/OVRR/DVRPA Safety: Melisse Baylor, M.D. Medical Officer CBER/OVRR/DVRPA Statistical: Sang Ahnn, Ph.D. Statistical Reviewer CBER/OBE/DB/VEB/VEB.

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FluMist® age extension

Five years & younger

May 16, 2007


Fda presentation
FDA presentation

Efficacy: Therese Cvetkovich, M.D.

Medical Officer CBER/OVRR/DVRPA

Safety: Melisse Baylor, M.D.

Medical Officer CBER/OVRR/DVRPA

Statistical: Sang Ahnn, Ph.D.

Statistical Reviewer CBER/OBE/DB/VEB/VEB


Flumist efficacy supplement
FluMist efficacy supplement

Efficacy and safety

  • MICP 111: Culture confirmed endpoint, TIV control, relative efficacy and safety, 6m-59m

  • D153-P501: Culture confirmed endpoint, placebo controlled, efficacy and safety in 12m-35 m.

  • AV006:Culture confirmed endpoint, placebo controlled, efficacy and safety 15m -71m, two years of data (reviewed in original BLA)

    Immunogenicity

  • Study AV018: concurrent administration of MMR and V with FluMist


Micp 111
MICP 111

  • Randomized 1:1

  • Double blinded

  • Safety and relative efficacy of FluMist against TIV 6 to 59 months of age

  • Stratified by

    • Age

      • 6-23m and 24-59m based on then current ACIP recommendations for yearly influenza vaccination

      • 24-35m and 36-59m based upon TIV dosing recommendation

    • Prior influenza vaccination

    • Country/geographic area

    • Wheezing history as defined in the protocol


Micp111 protocol definitions
MICP111Protocol definitions

  • Primary endpoint: relative efficacy of FluMist compared to TIV against culture confirmed influenza illness

  • Influenza illness:

    • culture confirmed modified CDC-ILI,

    • caused by community-acquired wild-type strains antigenically similar to those contained in the vaccine

    • occurred during the influenza surveillance period and at least 14 days after the last required vaccination


Micp111 protocol definitions1
MICP111Protocol definitions

Modified CDC ILI

  • Fever (38˚C equivalent)

    and

  • Cough, sore throat, or runny nose/nasal congestion.


Micp 111 protocol definitions
MICP 111Protocol definitions

Qualifying symptoms for obtaining nasal swab during influenza surveillance period:

  • New onset of one or more:

    • fever ≥ 38C, any wheezing, shortness of breath, pulmonary congestion, pneumonia, ear infection

  • New onset of two or more:

    • runny nose, sore throat, cough, myalgia, chills, headache, irritability, decreased activity, vomiting


Micp 111 analysis populations
MICP 111Analysis populations

As treated population (ATP):Analysis of primary endpoint

  • Randomized subjects who:

    • ≥ 1 surveillance contact on or after November 1, 2004 and 14 days after the final vaccination

    • Did not experience a major protocol violation

  • Analyzed according to the active study vaccination received at dose 1 (“as-treated”)

    Major protocol violation: one likely to affect the clinical observations or response to vaccination of the subject.

    Intent to treat (ITT)

  • All randomized subjects

  • Analyzed regardless of active study vaccine given (“as-randomized”)


Micp 111 results
MICP 111Results

  • 220 investigators (108 US, 15 Asia, 97 Europe/Middle East)

    • 49% US, 6% Asia, 45% Europe/ME

  • Initiated October 20, 2004, completed August 31, 2005

    • First dose Oct. 20-29, 2004

    • Second dose Nov. 04 to Jan. 05

  • 2004-05 formulation: both vaccines

  • One dose if previously vaccinated; two doses if not


Micp 111 results population demographics
MICP 111Results: population demographics

  • 48% 6 – 23 m

  • 22% prior flu vaccination (one dose group)

  • 6% positive wheezing history (protocol definition)

  • 80% white, non-Hispanic, 4% Black, 6% Hispanic, 7% Asian

  • 51% male

  • 5% underlying disease: mostly chronic lung disease (asthma)


Micp111 results populations for analysis
MICP111 resultsPopulations for analysis


Micp 111 tiv availability 2004 2005
MICP 111TIV availability 2004-2005

  • 6 – 35 months: 0.25 mL

  • 36- 59 months: 0.5 mL

  • 0.25 mL dose only available in US and Asia

  • Therefore, enrollment in US and Asia restricted to infants/children 6-35 m


MICP 111Primary endpoint: Positive influenza culture for strains antigenically related to those contained in the vaccine plus modified CDC ILI, 14 days or more after last vaccination (ATP); from applicant’s analyses


Micp 111 primary endpoint antigenically dissimilar strains
MICP 111Primary endpoint, antigenically dissimilar strains






Micp 111 efficacy conclusions
MICP 111 all strainsEfficacy conclusions

  • Large adequate and well-controlled study

  • Active control: relative efficacy

  • Multiple geographic sites

  • Objective clinical endpoint

  • Prevented culture-confirmed CDC ILI

  • Efficacy against A strains; similar (79%) and dissimilar (89%);

  • B strains: Similar and dissimilar: 16%

  • Adequate power in both prespecified age subgroups


D153 p501 design
D153-P501 all strainsDesign

  • Phase 3 randomized double-blinded study

  • Multiple countries in Asia between September 30, 2000 and May 31, 2003

  • Healthy 12- 36 month old children

  • Primary efficacy endpoint: culture confirmed ILI during the first influenza season


D153 P501 all strainsPrimary endpoint: culture confirmed ILI due to antigenically similar influenza strains


D153 p 501 culture confirmed ili due to any wild type influenza strain
D153 P 501 all strainsCulture confirmed ILI due to any wild type influenza strain


Av006 study design
AV006 all strainsStudy Design

Phase 3, randomized (2:1), placebo controlled

  • Conducted over two years, 1996 – 97 and 1997 – 98.

  • Population: 15-71 months of age

  • Primary endpoint: culture-confirmed influenza illness due to wild-type virus subtypes antigenically similar to the strains contained in the vaccine.


Av006 efficacy year 1
AV006 all strainsEfficacy Year 1


Av006 efficacy year 2
AV006 all strainsEfficacy Year 2


Efficacy conclusions
Efficacy conclusions all strains

  • AV006:

    • Adequate and well-controlled study

    • Objective clinical endpoint

    • Two years

    • Efficacy against culture confirmed ILI

    • A strains

      • similar 95% -dissimilar 86%

    • B strain: similar 91%

  • D153P501

    • Adequate and well controlled study

    • Placebo controlled: absolute efficacy

    • Objective clinical endpoint

    • Efficacy against similar and dissimilar w-t influenza strains


Overall flumist efficacy conclusions
Overall FluMist efficacy conclusions all strains

  • Efficacy against culture confirmed ILI

  • Three years of data

    • Different community acquired influenza strains, antigenically similar and antigenically dissimilar


Fda clinical analysis of flumist safety

FDA Clinical Analysis of FluMist Safety all strains

Melisse Baylor, MD

Medical Officer

DVRPA, OVRR, CBER

VRBPAC

May 16, 2007


Fda safety review
FDA Safety Review all strains

  • Studies:

    • MI-CP111

    • D153-P501

    • AV006

  • Study MI-CP111:

    • Reactogenicity Events and Adverse Events

    • Significant New Medical Conditions

    • Serious AEs and Deaths

    • Analysis of Wheezing

    • Analysis of Hospitalizations


Study mi cp111 exclusion criteria
Study MI-CP111: Exclusion Criteria all strains

  • Excluded children with:

    • History of severe asthma

    • Medically diagnosed wheezing in 42 days prior to study entry

    • Bronchodilator or steroid use in 42 days prior to study entry


Safety monitoring in mi cp111
Safety Monitoring in MI-CP111 all strains

  • Reactogenicity Events – 42 days

    • fever, runny/stuffy nose, sore throat, cough, wheezing, vomiting, headache, muscle aches, chills, decreased activity, irritability, abdominal pain, decreased appetite, injection site signs/symptoms

  • Adverse Events – 42 days

  • Medically significant wheezing – 42 days

  • Significant New Medical Conditions – 180 days

  • Serious AEs – 180 days


Reactogenicity events
Reactogenicity Events all strains

  • Reactogenicity events more common in FluMist recipients than TIV recipients

    • After the first dose: 69% vs 63%

    • After the second dose: 55% vs 51%

  • Reactogenicity events reported more frequently in FluMist recipients than TIV recipients

    • Runny / stuffy nose: 57% vs 46% after 1st dose

    • Low grade fever: 15% vs 12% after 1st dose

  • In subgroup of subjects <24 months of age

    • Higher frequency of all REs (75% of FluMist recipients and 67% of TIV recipients)

    • Cough also more common in FluMist recipients (32%) than in TIV recipients (30%)


Adverse events in the 28 days post vaccination
Adverse Events in the 28 Days all strainsPost-Vaccination



Serious adverse events
Serious Adverse Events all strains

  • 2 Deaths –

    • One each study arm

    • Both accidental - neither vaccine related

  • Serious AEs

    • In 180 days post-vaccination: 3.3% of subjects in FluMist arm and 3.1% in TIV arm

    • In 42 days post-vaccination: 1.3% of subjects in FluMist arm and 1.3% in TIV arm

    • In 10 days post-vaccination: 0.3% of subjects in FluMist arm and 0.4% in TIV arm


Serious adverse events reported in 1 study subjects in 6 weeks post vaccination
Serious Adverse Events Reported in all strains≥ 1 Study Subjects in 6 Weeks Post-Vaccination


Definitions of wheezing
Definitions of Wheezing all strains

  • Medically significant wheezing: Applicant definition for wheezing on examination plus one of the following: signs of respiratory distress (↑ respiratory rate, retractions, dyspnea), hypoxemia (oxygen saturation < 95%), or new prescription for daily bronchodilator

    • Primary definition used by Applicant in safety analysis

  • All Wheezing: Applicant definition for the preferred terms asthma, bronchiolitis, bronchospasm, and wheezing;

    • Secondary safety endpoint for Applicant

    • Primary definition used by clinical reviewer


History of asthma safety population
History of Asthma all strainsSafety Population


Analysis of all wheezing events within 42 days after last vaccination
Analysis of All Wheezing Events all strains(Within 42 Days After Last Vaccination)




Duration in days of all wheezing events in 42 days post vaccination
Duration in Days of All Wheezing Events in 42 Days Post-Vaccination

Missing Data: 8% of FluMist events and 9% of TIV events





Additional analyses
Additional Analyses Post-Vaccination)

  • Increased wheezing and bronchiolitis in males compared to females in both arms

  • No difference in wheezing by race/ethnicity

  • Little difference in wheezing by country of origin

  • Upper and Lower respiratory tract events

    • Increased number of events of pulmonary congestion and sinusitis in FluMist arm

    • Few events of respiratory distress, hypoxia, and tachypnea




Number and percentage of subjects with any wheezing event within 42 days by history of wheezing
Number and Percentage of Subjects with Any Wheezing Event within 42 Days by History of Wheezing


Number and percentage of subjects with any wheezing event within 42 days by history of wheezing1
Number and Percentage of Subjects with Any Wheezing Event within 42 Days by History of Wheezing


Number of hospitalizations by age and time post vaccination 0 180 days after last vaccination
Number of Hospitalizations by Age and Time Post-Vaccination within 42 Days by History of Wheezing(0-180 Days After Last Vaccination)

*some subjects with hospitalizations in both time periods










Study av006
Study AV006 Vaccination

  • Study Design

    • Randomized, double-blind, placebo controlled

    • Enrolled children 15-71 months of age

    • Excluded children with hx of wheezing or bronchodilator use in prior 3 months

  • Results:

    • FluMist – 816 subjects, Placebo-410

    • No increase in respiratory events or asthma reported in FluMist recipients

    • 7 hospitalizations in FluMist arm vs. 3 in Placebo arm


Study d153 501
Study D153-501 Vaccination

  • Study Design

    • Randomized, double-blind, placebo controlled

    • Enrolled children 12-35 months of age

    • Excluded children with hx of wheezing in prior 2 weeks

    • Followed AEs for 11 days post-vaccination

  • Results:

    • FluMist – 1901 subjects, Placebo-1273

    • No increase in bronchospasm, bronchiolitis, or pneumonia in FluMist recipients

    • No difference in hospitalizations between arms


Summary
Summary Vaccination

  • FluMist was safe and effective in subjects 24 months of age and older

  • In Study MI-CP111, in subjects <24 months of age, there were:

    • Increased hospitalizations

    • Increased severity of wheezing

    • Increased severity of respiratory events

  • History of wheezing was poorly predictive of wheezing post-vaccination


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