INFLUENZA VACCINE, injection, 0.5 mL, Fluarix, Fluvax, Influvac, Vaxigrip, November 2007
Public summary document for INFLUENZA VACCINE, injection, 0.5 mL, Fluarix, Fluvax, Influvac, Vaxigrip, November 2007
Page last updated: 14 March 2008
Public Summary Document
Product: INFLUENZA VACCINE, injection, 0.5 mL, Fluarix, Fluvax, Influvac, Vaxigrip
Sponsor: Influenza Specialist Group
Date of PBAC Consideration: November 2007
1. Purpose of Application
The submission sought to extend the current National Immunisation Program (NIP) listing of influenza vaccination to include all Australians over the age of 50 years.
2. Background
Influenza vaccination 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 at-risk Aboriginal and Torres Strait Islander persons aged 15-49 years. Influenza vaccination has also been available on the PBS since the early 1980’s as a restricted benefit for persons at special risk of adverse consequences from infections of the lower respiratory tract.
3. Registration Status
Influenza vaccination is registered for the prevention of influenza caused by Influenza Virus, Types A and B.
4. Listing Requested and PBAC’s View:
Funding under the NIP for universal vaccination of all persons aged 50 years and older
in Australia.
The PBAC did not comment on the requested restriction.
5. Comparator
6. Clinical Trials
The submission presented the results of sixteen randomised controlled trials comparing
influenza vaccination to placebo or to no intervention. Of these sixteen trials, four
trials were performed in high risk patients (asthma, chronic obstructive pulmonary
disease, multiple myeloma, and multiple sclerosis) and one trial was a single arm
study. A Cochrane review (2007) included 48 trials. Eleven trials in the submission
were included in the Cochrane review. On the other hand, the review excluded a paper
by Wilde et al, but the submission included it. A list of the trials presented in
the submission is shown below:
Publications presented in the submission
|
Trial/First author |
Protocol title |
Publication citation |
|---|---|---|
|
Randomised controlled trials |
||
|
Abadoglu et al 2004 |
Influenza vaccination in patients with asthma: Effect on the frequency of upper respiratory tract infections and exacerbations |
Journal of Asthma 41: 279–283 |
|
Allsup et al 2003 |
Cost-benefit evaluation of routine influenza immunisation in people 65-74 years of age, |
Health Technology Assessment 7: 65–78 |
|
Allsup et al 2004 |
Is influenza vaccination cost effective for healthy people between ages 65 and 74 years? A randomised controlled trial, |
Vaccine 23: 639–645 |
|
Allsup et al 2001 |
Side effects of influenza vaccination in healthy older people: A randomised single-blind placebo-controlled trial |
Gerontology 47: 311-314 |
|
Bridges et al 2000 |
Effectiveness and cost-benefit of influenza vaccination of healthy working adults: A randomised controlled trial |
Journal of the American Medical Association 284: 1655–1663 |
|
Cohen et al 2003 |
Influenza vaccination in an occupational setting: Effectiveness and cost-benefit study |
Journal of Occupational Health and Safety Australia and New Zealand 19: 167–182 |
|
Edwards et al 1994 |
A randomised controlled trial of cold-adapted and inactivated vaccines for the prevention of influenza A disease, |
Journal of Infectious Diseases 169: 68–76 |
|
Govaert et al 1994 |
The efficacy of influenza vaccination in elderly individuals: A randomised double-blind placebo-controlled trial |
Journal of the American Medical Association 272: 1661–1665 |
|
Govaert et al 1993 |
Adverse reactions to influenza vaccine in elderly people: randomised double blind placebo controlled trial |
British Medical Journal 307: 998–990 |
|
Mesa Duque et al 2001 |
[Effectiveness of an influenza vaccine in a working population in Colombia] |
Revista panamericana.de salud pblica Pan [American Journal of Public Health 10: 232–239] |
|
Miller et al 1997 |
A multicenter, randomised, double-blind, placebo-controlled trial of influenza immunization in multiple sclerosis |
Neurology 48: 312–314 |
|
Mixeu et al 2002 |
Impact of influenza vaccination on civilian aircrew illness and absenteeism |
Aviation Space and Environmental Medicine 73: 876–880 |
|
Musto et al 1997 |
Vaccination against influenza in multiple myeloma |
British Journal of Haematology. 97: 505–506 |
|
Nichol et al 1995 |
The effectiveness of vaccination against influenza in healthy, working adults, |
New England Journal of Medicine 333: 889–893 |
|
Nichol et al 1996 |
Side effects associated with influenza vaccination in healthy working adults: A randomised, placebo-controlled trial, |
Archives of Internal Medicine 156: 1546-1550 |
|
Powers et al 1995 |
Influenza A virus vaccines containing purified recombinant H3 hemagglutinin are well tolerated and induce protective immune responses in healthy adults |
Journal of Infectious Diseases 171: 1595–1599 |
|
Praditsuwan et al 2005 |
The efficacy and effectiveness of influenza vaccination among Thai elderly persons living in the community |
Journal of the Medical Association of Thailand 88: 256–264 |
|
Weingarten et al 1988 |
Do hospital employees benefit from the influenza vaccine? A placebo-controlled clinical trial |
Journal of General Internal Medicine 3: 32–37 |
|
Wilde et al 1999 |
Effectiveness of influenza vaccine in health care professionals: A randomised trial |
Journal of the American Medical Association 281: 908–913 |
|
Wongsurakiat et al 2003 |
Economic evaluation of influenza vaccination in Thai chronic obstructive pulmonary disease patients |
Journal of the Medical Association of Thailand 86: 497–508 |
|
Wongsurakiat et al 2004 |
Adverse effects associated with influenza vaccination in patients with COPD: A randomised controlled study |
Respirology 9: 550–556 |
|
Wongsurakiat et al 2004 |
Acute respiratory illness in patients with COPD and the effectiveness of influenza vaccination: A randomised controlled study |
Chest 125: 2011–2020 |
|
Meta-analysis |
||
|
Demicheli et al 2004 |
Vaccines for preventing influenza in healthy adults |
Cochrane Database of Systematic Reviews Issue 3: 1–66 |
|
Jefferson et al 2007 |
Vaccines for preventing influenza in healthy adults |
Cochrane Database of Systematic Reviews Issue 2: 1-81 |
7. Results of Trials
The main outcome discussed in the submission was influenza like illness (ILI) which
was a primary or secondary outcome of all trials. Other Secondary outcomes included
serologically confirmed influenza and hospitalisations due to ILI.
The results of the key trials are summarised in the tables below.
Results of influenza-like illness cases across the direct randomised trials
|
Trial ID |
Vaccine |
Placebo or no intervention n/N (%) |
Risk difference |
Relative risk |
|---|---|---|---|---|
|
Key evidence |
||||
|
Allsup 2003 |
5/552 (0.9) |
2/177 (1) |
0.00 |
0.80 |
|
Bridges 2000a |
161/595 (27) |
132/589 (22) |
0.05 |
1.21 |
|
Bridges 2000b |
82/587 (14) |
128/604 (21) |
–0.07 |
0.66 |
|
Cohen 2003 |
104/296 (35) |
101/301 (34) |
0.02 |
1.05 |
|
Edwards 1994a |
75/878 (8.5) |
92/878 (10) |
–0.02 |
0.82 |
|
Edwards 1994b |
89/1060 (8) |
119/1064 (11) |
–0.03 |
0.75 |
|
Edwards 1994c |
122/1126 (11) |
125/1125 (11) |
0.00 |
0.98 |
|
Edwards 1994d |
75/1016 (7) |
93/1016 (9) |
–0.02 |
0.81 |
|
Govaert 1994 |
17/927 (2) |
31/911 (3) |
–0.02 |
0.54 |
|
Mesa Duque 2001 |
194/247 (79) |
225/246 (91) |
–0.13 |
0.86 |
|
Mixeu 2002 |
86/405 (21) |
98/408 (24) |
–0.03 |
0.88 |
|
Nichol 1995 |
249/424 (59) |
287/425 (68) |
–0.09 |
0.87 |
|
Powers 1995 |
4/26 (15) |
6/24 (25) |
–0.10 |
0.62 |
|
Praditsuwan 2005 |
13/330 (4) |
26/305 (9) |
–0.05 |
0.46 |
|
Case specific definition, studies with high risk patients excluded |
||||
|
Pooled result from random effects model |
–0.02 |
0.87 |
||
|
p value |
0.002 |
0.002 |
||
|
Chi square (Q) for heterogeneity: p = |
0.0002 |
0.02 |
||
In the analysis of case specific definition for all studies, there was a significant
difference in the number of patients with influenza-like illness (ILI) in the vaccine
group compared with the placebo/no intervention group (p <0.002). The analysis shows
there to be a risk difference (RD) of –2% (95% CI: [–4%, –1%]) and relative risk (RR)
of 87% (95% CI: [79%, 95%]) with vaccination. However, significant heterogeneity was
detected between the studies (p = 0.005).
The Jefferson 2007 Cochrane review found a RR for ILI of 77% (95% CI: [68%, 87%])
for inactivated parenteral vaccine versus placebo or no intervention.
Results of influenza cases serologically confirmed across the direct randomised trials
|
Trial ID |
Vaccine |
Placebo or no intervention |
Risk difference |
Relative risk |
|---|---|---|---|---|
|
Key evidence |
||||
|
Bridges 2000a1 |
3/595 (0.5) |
6/589 (1) |
–0.01 |
0.49 |
|
Bridges 2000b1 |
2/587 (1) |
14/604 (10) |
–0.02 |
0.15 |
|
Edwards 1994a2 |
6/878 (0.7) |
28/878 (3) |
–0.03 |
0.21 |
|
Edwards 1994b2 |
9/1060 (0.8) |
29/1064 (3) |
–0.02 |
0.31 |
|
Edwards 1994c2 |
8/1126 (0.7) |
32/1125 (3) |
–0.02 |
0.25 |
|
Edwards 1994d2 |
4/1016 (0.4) |
18/1016 (2) |
–0.01 |
0.22 |
|
Govaert 19941 |
41/927 (4) |
80/911 (9) |
–0.04 |
0.50 |
|
Powers 19952 |
0/26 (0%) |
3/24 (13) |
–0.13 |
0.13 |
|
Praditsuwan 20051 |
7/330 (2) |
19/305 (6) |
–0.04 |
0.34 |
|
Wilde 1999a1 |
2/52 (4) |
14/50 (28) |
–0.24 |
0.14 |
|
Wilde 1999b1 |
0/51 (0) |
4/52 (8) |
–0.08 |
0.11 |
|
Wilde 1999c1 |
1/78 (1) |
7/78 (9) |
–0.08 |
0.14 |
|
Pooled result from random effects model |
–0.03 |
0.32 |
||
|
p value |
<0.00001 |
<0.00001 |
||
|
Chi square (Q) for heterogeneity: p = |
<0.00001 |
0.39 |
||
Wilde 1999, serological cases of A and B influenza combined 1 Influenza confirmed
from blood samples pre and post vaccination 2 Influenza confirmed from vaccines presenting
with influenza like illness
A significantly greater proportion of patients were diagnosed with laboratory confirmed
influenza in the placebo/no intervention group compared with the vaccine group (p<0.0001).
For patients receiving the vaccine compared with those patients who did not receive
the vaccine, the analysis shows there to be a RD of –3% (95% CI: [–4%, –1%]) and RR
of 32% (95% CI: [25%, 41%]) of contracting laboratory confirmed influenza.
No heterogeneity was detected between the studies when an analysis of risk difference
was performed (p = 0.39), although an analysis of relative risk did detect a significant
amount of between-study variance (p<0.00001).
Results of hospitalisations across the direct randomised trials
|
Trial ID |
Vaccine |
Placebo or no intervention |
Risk difference |
Relative risk |
|---|---|---|---|---|
|
Key evidence |
||||
|
Allsup 20032 |
0/552 (0) |
0/177 (0) |
0.00 [–0.01, 0.01] |
Not estimable |
|
Bridges 2000a2 |
1/595 (0.2) |
0/589 (0) |
0.00 [0.00, 0.01] |
2.97 |
|
Bridges 2000b2 |
0/587 (0) |
0/604 (0) |
0.00 [0.00, 0.00] |
Not estimable |
|
Supportive trials |
||||
|
Musto 19971, 3 |
2/25 (8) |
12/25 (48) |
–0.40 |
0.17 |
|
Wongsurakiat 20041,2 |
2/62 (3) |
5/63 (8) |
–0.05 |
0.41 |
|
High risk excluded |
||||
|
Pooled result from random effects model |
0.00 [0.00, 0.00] |
2.97 |
||
|
p value |
0.63 |
0.50 |
||
|
Chi square (Q) for heterogeneity: p = |
0.83 |
n/a |
||
|
All studies |
||||
|
Pooled result from random effects model |
0.00 [-0.02, 0.01] |
0.32 |
||
|
p value |
0.74 |
0.01 |
||
|
Chi square (Q) for heterogeneity: p = |
<0.00001 |
0.25 |
||
1 High risk study;2Hospitalisation due to influenza like illness; 3Reason for hospitalisation
not reported
A significant relative risk of hospitalisation (32%; 95% CI: [13%, 78%]) was detected
in the vaccine group compared with the placebo/no intervention group, in the analysis
of all studies (p = 0.01). However, when high risk studies (Musto and Wongsurakiat)
were excluded from the analysis, no significant difference between the two groups
was detected (p = 0.50).
The Jefferson 2007 Cochrane review showed a relative risk of 89% (95% CI: [65%, 120%])
in hospitalisation attributed to vaccination. This effect was largely driven by a
study from 1970 which was undertaken during the 1968/1969 pandemic in the USA. Without
this study included, there were no differences in hospitalisations between the treatment
arms.
In the analysis of all studies, there was no significant difference in the number
of patient deaths between the vaccine group and the placebo/no intervention group
(p = 0.98). Moreover, there was no significant difference between the two treatment
arms when the high risk studies were excluded (p = 0.41).
Adverse events were localised, not systemic reactions. There was no evidence to suggest
that the rare adverse reactions that occurred were a result of influenza vaccination.
Four types of local adverse events were experienced by a significantly greater proportion
of patients in the vaccine group compared to the comparator. Arm soreness/tenderness
differed significantly between the two groups (p<0.00001) as well as erythema (p=0.001),
induration (hardening of soft tissue) (p<0.00001) and warm feeling (p=0.0002). Significant
heterogeneity was detected between the studies for each of these events. Some individual
studies showed significant differences in the relative risk of further adverse events,
such as itching, numbness, oedema, myalgia, fever, headache, sore throat, fatigue
or indisposition, coryza, chills, nausea, diarrhoea, cough, rhinorrhea, rash, malaise
and other, undescribed adverse events.
For the PBAC’s comments on these results, see Recommendation and Reasons.
8. Clinical Claim
The submission claimed that influenza vaccine is therapeutically superior to placebo. The PBAC considered that there was some uncertainty about this clinical claim, see Recommendation and Reasons.
9. Economic Analysis
The submission presented a stepped economic evaluation as the modelled evaluation.
The choice of a cost-utility approach was considered valid. The resources included
were vaccine costs, vaccine administration costs, hospital services and diagnostic
tests and imaging.
The submission calculated a base case modelled incremental discounted cost/extra discounted
QALY of less than $15,000, increasing to $15,000 - $45,000 if the values of the Jefferson
(2007) Cochrane review were used (23% ILI, 11% hospitalisation, 20% pneumonia, compared
with 13%, 68% and 68% in the submission, respectively).
The PBAC considered that there was high sensitivity of the cost per QALY saved due
to the assumptions used in the model, see Recommendation and Reasons.
10. Estimated PBS Usage and Financial Implications
The financial cost per year to the NIP excluding co-payments minus any cost due to the current policy was estimated to be in the range of $10 - $30 million in Year 5.
11. Recommendation and Reasons
The PBAC observed that the inclusion criteria for the trials included a wide and varied
range of people of all ages and were therefore not representative of the group for
whom listing in the NIP was sought.
The PBAC considered that, although not unreasonable, there is some uncertainty about
the submission’s clinical claim that influenza vaccination has significant advantages
in effectiveness over placebo or no intervention and uncertain toxicity. This was
because the claim was based on ILI (which was not confirmed in all the trials and
its definition was variable from study to study) and laboratory-confirmed influenza,
but there was no difference in hospitalisations or deaths between vaccinated and unvaccinated
individuals, if patients at high risk were excluded from the meta-analyses.
The PBAC accepted that the model is driven by influenza-attributable mortality and
hospitalisation and these are determined by laboratory-confirmed influenza rates rather
than ILI. However, there were a number of problems with the assumptions used in the
model. For example, similar efficacy was assumed for the 50-65 year-old age group
as for 18-65 year-old age group based upon almost ‘similar’ immunogenicity response
rate rather than geometric mean titres. Further, immunosenescence was assumed to not
commence until a patient reaches 65 years and then to decline precipitously.
The PBAC considered that the pivotal assumption that amongst the additionally vaccinated
Australian population a clinically observed 68% reduction in laboratory confirmed
cases of influenza in healthy patients with vaccination leads to a 68% reduction in
influenza related hospitalisations and deaths, was insufficiently substantiated. The
PBAC considered that acceptance of this assumption implies that the mortality and
hospitalisation rates from influenza are independent of immune response to vaccination.
The PBAC agreed it is likely that the patients with no immune response to vaccination
in the vaccination setting are also those who were more likely to have had a higher
mortality rate and more severe cases in the non-vaccination setting – hence the rate
of mortality amongst those who contract influenza in the vaccination arm may be expected
to be higher than in those who contract influenza in the non-vaccination arm. Further,
it is likely that the patients with no immune response to vaccination in the vaccination
setting are also those who were more likely to be more severe cases and present to
hospitals in the non-vaccination setting – hence the rate of hospitalisation and complexity
of the hospitalised cases (higher cost per hospitalisation) amongst those who contract
influenza in the vaccination arm may be expected to be higher than amongst those who
contract influenza in the non-vaccination arm.
The PBAC also noted that the model was highly sensitive to hospitalisation rates post
influenza.
The PBAC therefore rejected the submission because of uncertainty in clinical benefits
in terms of hospitalisation and mortality and uncertainty about the results of the
modelled economic evaluation, because of use of an insufficiently substantiated reduction
in hospitalisation and mortality rates and the lack of inclusion of a decrement of
response to the vaccine with age.
Despite rejecting the submission, the PBAC had some sympathy with the intention of
immunising more at-risk individuals and recommended that consideration be given to
establishing a subsidy arrangement ‘between’ the PBS and NIP mechanisms that would
more effectively target this group.
12. 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.
13. Sponsor’s Comment
The Influenza Specialist Group (ISG) applied for an extension of the National Immunisation
Program (NIP) to include influenza vaccination for all Australians aged 50 - 64 years.
This was based on its study indicating that this would constitute a cost-effective
extension of the program and previous studies indicating that age-based targeting
would be the most effective means of increasing vaccination in the substantial high-risk
population within this age cohort.
Although the application was rejected by the Pharmaceutical Benefits Advisory Committee
(PBAC), the ISG would like to reaffirm its strong focus on increasing vaccination
uptake among Australians at risk of severe complications from influenza and will continue
to work to this end.
