Influenza vaccine, injection in pre-filled syringe, 15 micrograms/strain/0.1 mL (containing A/New Caledonia/20/99, A/Wisconsin/67/2005, B/Malaysia/2506/2004 like strains), Intanza®
Public summary document for Influenza vaccine, injection in pre-filled syringe, 15 micrograms/strain/0.1 mL (containing A/New Caledonia/20/99, A/Wisconsin/67/2005, B/Malaysia/2506/2004 like strains), Intanza®
Page last updated: 30 October 2009
Public Summary Document
Product: Influenza vaccine, injection in
pre-filled syringe, 15 micrograms/strain/0.1 mL (containing A/New
Caledonia/20/99, A/Wisconsin/67/2005, B/Malaysia/2506/2004 like
strains), Intanza®
Sponsor: Sanofi Pasteur Pty Ltd
Date of PBAC Consideration: July 2009
1. Purpose of Application
To request inclusion of an influenza vaccine administered via the
intradermal route on the National Immunisation Program (NIP) for
vaccination against influenza for patients aged 65 years and
older.
2. Background
Influenza vaccine administered via the intradermal route had not
previously been considered by the PBAC.
Influenza vaccination administered via the intramuscular route is
currently funded by the Commonwealth Government as part of the NIP
for all Australians aged 65 years and over, Aboriginal and Torres
Strait Islander persons aged 50 years and over and Aboriginal and
Torres Strait Islander persons aged 15 – 49 years considered
at risk. Influenza vaccination administered via the intramuscular
route has also been available on the PBS since the early 1980s and
is currently available as a restricted benefit for persons at
special risk of adverse consequences from infections of the lower
respiratory tract.
3. Registration status
Intradermal (ID) influenza vaccine 15 microgram was TGA registered
on 14 April 2009 for the prophylaxis of influenza in individuals
from 60 years and over. The 9 microgram preparation was also TGA
registered on this date for the prophylaxis of influenza in adults
from 18 to 59 years of age. Their use in Australia should be based
on NHMRC recommendations for influenza vaccination as published in
the current Australian Immunisation Handbook.
4. Listing requested and PBAC’s View
The requested National Immunisation Program indication is:
Universal vaccination against influenza of all persons aged 65
years and older.
See Recommendation and Reasons for PBAC’s
view.
5. Clinical place for the proposed therapy
An alternative to intramuscular vaccination in people aged 65 years
or over.
6 Comparator
Current NIP-funded influenza vaccines for persons aged greater than
or equal to 65 years, defined as 15 microgram intramuscular (IM)
influenza vaccines in the submission. Vaxigrip®, an
IM vaccine from the same sponsor, is used in the submission as a
proxy for 15 microgram IM vaccines.
7. Clinical trials
The submission presented 2 randomised trials (one Australian GID16,
one European GID17) comparing Intanza 15 microgram ID vaccine with
Vaxigrip 15 microgram IM vaccine and an integrated immunogenicity
analysis of the 2 trials (GID16 and GID17 first vaccination –
the global integrated analysis).
Details of the published trials presented in the submission are in
the following table:
| Trial ID/ Lead author | Protocol title/ Publication title | Publication citation |
| Direct randomised trials | ||
| GID16 Holland (2008) | Intradermal influenza vaccine administered using a new microinjection system produces superior immunogenicity in elderly adults: A randomised controlled trial. | The Journal of Infectious Diseases 2008; 198:650-658 |
| GID17 Arnou (2009) | Intradermal influenza vaccine for older adults: a randomized controlled multicenter phase III study. | Submitted in October 2009 for publication in Vaccine |
8. Results of trials
The submission claimed that the proposed 15 microgram ID vaccine
was statistically non-inferior and superior to Vaxigrip 15
microgram IM vaccine. Outcome results were presented for the
geometric mean titres (GMT) and seroprotection rates against the 3
strains of influenza (A/H1N1, A/H3N2 and B) before vaccination (day
0) and at 21 days post-vaccination in the direct randomised
trials.
As the lower bound of the 95 % CI of the difference between the
log10-transformed post-vaccination GMTs (ID minus IM)
were greater than –0.176 for all the 3 strains, the
submission claimed that Intanza 15 microgram ID vaccine was
non-inferior to Vaxigrip 15 microgram IM vaccine in terms of
post-vaccination GMTs 21 days after vaccination.
As the lower 95 % CI of the difference between the
log10-transformed post-vaccination GMTs
[log10(GMTID)−log10(GMTIM)]
were greater than 0 for at least two strains in GID16, the
submission further claimed that Intanza 15 microgram ID vaccine was
superior to the Vaxigrip 15 microgram IM vaccine in terms of
post-vaccination GMTs 21 days after vaccination in GID16.
As the lower bound of the 9 5% CI of the difference between the
post-vaccination seroprotection rates (ID minus IM) was greater
than 0 for the 3 strains in both the global integrated analysis and
the GID17 (a phase III trial) trial and greater than 0 for 2
strains in GID17 (a phase II trial) trial, the submission further
claimed that Intanza 15 microgram ID vaccine was superior to
Vaxigrip 15 microgram vaccine in terms of seroprotection rates 21
days post vaccination.
The claim of superiority was based on serological outcomes. No
controlled trials demonstrating a greater reduction in influenza
disease after vaccination were presented. It was noted that
seroprotection rates improved with both vaccines, depending on the
strain, from a baseline of approximately 30, 45, and 12 to 70-90 %.
An additional approximate 6 % improvement in seroprotection rate
was achieved with the ID vaccine compared to the IM vaccine.
The evaluation of antibody persistence in a subset of patients in
GID17 in terms of decline in GMTs, seroprotection rates and GMTRs
over time was presented. The submission reported that:
More than 60 % of participants remained seroprotected against both
A strains at 3 (D90) and 6 months (D180) post vaccination for both
ID and IM injection. Seroprotection for the B strain was achieved
only for ID vaccine at 21 days. Seroprotection rates were
numerically lower in the 15 microgram ID group at 6 and 12 months,
although confidence intervals were generally overlapping.
Anti-haemagglutinin antibody titres (Anti-HA antibodies) were
higher in the 15 microgram ID group than in the 15 microgram IM
group for both A strains at 21 days and 3 months (the influenza
season) post vaccination. GMTs for the B strain were slightly
higher from Day 90 onwards in the IM group compared to the ID
group
The decline of antibodies was similar between the 15 microgram ID
and 15 microgram IM vaccines for the two A strains. However, the
decline was slightly higher in the ID group than in the IM
group.
With respect to adverse events, the submission reported that the
risks of serious adverse events (SAE) with ID and IM vaccines were
comparable and that none of the SAEs were considered related to the
study vaccine apart from 2 cases of non-fatal SAEs with the ID
vaccine.
The submission noted that although the injection site reactions
were in general higher with the proposed ID vaccine than the IM
vaccine, these reactions were transient and recovery was
spontaneous. The submission therefore claimed that the overall
safety profiles of the proposed 15 microgram ID vaccine and
Vaxigrip 15 microgram IM vaccine were comparable.
The most common solicited injection site reactions were erythema,
induration and swelling for the ID group and erythema, pain and
induration for the IM group. As for solicited systemic reactions,
the most common were headache, myalgia and malaise for both the ID
and IM groups and the percentage of subjects experiencing these
reactions in both groups was comparable. The submission reported
that the greater injection site reactions with the proposed ID
vaccine were expected as the ID vaccine involves direct injection
of antigen into the dermis which is more immunogenic than the deep
muscles. In addition, most injection site reactions occurred within
24 hours after vaccination, were present for a maximum of 3 days,
and resolved spontaneously. Over 80 % of the participants in GID17
(first vaccination) considered the pain and injection site
reactions “totally acceptable” (greater than or equal
to 81 % and greater than or equal to 85 % in the ID 15 microgram
and IM 15 microgram groups respectively, results from the Vaccine
Comfort Questionnaire). As for the solicited systemic reactions,
most occurred after less than 3 days of vaccination, lasted for
less than 3 days and were mild to moderate in severity.
The submission did not provide any data beyond the direct
randomised trials on potential safety concerns beyond those
identified in the clinical trials.
9. Clinical Claim
The submission claimed that Intanza 15 microgram ID vaccine was
superior to the existing NIP-listed influenza vaccines in efficacy
and with equivalent safety.
For PBAC’s views see Recommendation and
Reasons.
10. Economic Analysis
A stepped economic evaluation was presented. The model used was a
decision tree model which compared the practice with the proposed
ID listing and the existing vaccination practice with IM vaccines
in persons aged greater 65 years and over.
In the absence of patient-relevant clinical trial outcomes,
surrogate Haemagglutination-Inhibition (HI) antibody titres were
applied to the HI Protection Model to estimate the relative
increase in vaccine efficacy (ID versus IM vaccines), which was
then used to generate differential patient-relevant clinical
outcomes. The HI protection model derived relationships between HI
titres and probability of protection for populations aged 65 years
and older for the indication of three strains from 15
studies.
In the modelled evaluation, the intradermal vaccine was claimed to
be dominant over the intramuscular vaccine (more effective and less
costly) in terms of life years gained and quality adjusted life
years gained.
Among the main drivers identified for the model were the relative
increase in vaccine efficacy (RIVE) (ID versus IM vaccines) and the
relative risk of laboratory confirmed influenza (LCI) with IM
vaccination.
11. Estimated PBS Usage and Financial Implications
The number of eligible persons aged 65 years or over likely to take
up NIP-funded vaccination against influenza was estimated to be
between 2 and 3 million people per year.
The likely acquisition cost of the proposed vaccine was as the
lower end of the range between $30 million to $60 million per year,
while the net financial cost per year for the NIP (including
cost-offsets with the substitution of IM vaccines) was less $10
million per year in the first year of listing.
12. Recommendation and Reasons
The PBAC recommended the listing of the influenza intradermal (ID)
vaccine on the NIP on the basis of cost-minimisation versus the
intramuscular (IM) vaccine.
The submission presented two randomised trials (GID16, GID17)
comparing Intanza
15 microgram ID vaccine with Vaxigrip 15 microgram IM vaccine and
an integrated immunogenicity analysis of the two trials (GID16 and
GID17 first vaccination). The submission’s claim of
superiority was based on serological outcomes. The PBAC noted that
seroprotection rates improved with both vaccines, and although
there was some heterogeneity at baseline, an additional approximate
6 % improvement in seroprotection rate was achieved with the ID
vaccine. No trials were presented to show that the ID formulation
was superior to the IM formulation in terms of reducing mortality,
morbidity or hospitalisation associated with influenza disease. The
PBAC agreed with the ATAGI advice, that the clinical significance
of such an increase in immunogenicity in the elderly population was
uncertain.
In terms of safety, there were more injection site reactions with
the ID vaccine than the IM vaccine. The PBAC noted that the
sponsors Pre-PBAC response highlighted the results of the
vaccination Comfort Questionnaire which showed the majority of
patients in the study group found the pain and injection site
reactions due to either vaccination to be “totally
acceptable” (greater than or equal to 81 % of the ID vaccine
compared with greater than or equal to 85 % of the IM vaccination
group).
The PBAC expressed concerns about the validity of the
Hemagglutination Inhibition (HI) protection model presented in the
submission. The model was based on data derived from studies
conducted from 1945 to 1997 with differing study designs and
different ways of measuring antibody titres. Only one of these
studies included subjects aged 65 years or over. The PBAC noted the
ATAGI advice that concluded that combining these data for the model
was of questionable validity and that it cannot be assumed that
data obtained for healthy persons predominantly aged 18-59 years
can be applied successfully to those aged 65 years or over. Given
the data used to derive the model was not representative of the
population for whom the listing was being sought and information
produced by the model was highly uncertain, the PBAC considered it
uninformative.
The PBAC noted the statement in the Pre-PBAC response regarding the
PBAC’s previous decision to recommend the listing of
Adacel® on the NIP based on immunogenicity outcomes.
The PBAC considered that this example was not applicable to the
current submission because Adacel was recommended on a
cost-minimisation basis, rather than cost-effectiveness as the
current submission requests. The submission claimed that an
approximate 6 % increase in seroprotection translated by the HI
protection model predicted an increase in effectiveness of 16.9 %.
The pre-PBAC response stated “Given that
“Intanza® achieved superior GMTs and also
improved the proportion who seroconvert by approximately 6
%”, superior vaccine efficacy and patient-relevant
clinical outcomes are plausible.” It was the PBAC’s
view that the submission had failed to present convincing evidence
of superior patient relevant outcomes. The PBAC also noted the
submission was seeking a price higher than the comparator. It was
the PBAC’s view that this higher price had not been justified
by the submission.
The PBAC acknowledged that the vaccine was effective but
uncertainty existed about the translation of the approximate 6 %
increase in seroprotection, into patient relevant outcomes in the
population for whom listing was sought, and concluded that the data
presented supported a cost-minimisation analysis rather than
cost-effectiveness.
Recommendation
Restriction: National Immunisation Program
Universal vaccination against influenza of all persons aged 65 years and older.
Pack size: 1
13. Context for Decision
The PBAC helps decide whether and, if so, how medicines should be
subsidised in Australia. It considers submissions in this context.
A PBAC decision not to recommend listing or not to recommend
changing a listing does not represent a final PBAC view about the
merits of the medicine. A company can resubmit to the PBAC or seek
independent review of the PBAC decision.
14. Sponsor’s Comment
Sanofi Pasteur acknowledges that the PBAC has given a positive recommendation for Intanza on a cost-minimisation basis. The sponsor is disappointed though that the PBAC was unable to recommend listing Intanza on cost-effectiveness based on the superior seroprotection of ID versus IM vaccines shown in the (GID 16 and GID 17) clinical trials.
