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
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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
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
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
|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
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.
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.