Pneumococcal polysaccharide conjugate vaccine, 13-valent adsorbed, pre-filled syringe, 0.5 mL, Prevenar 13®
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Product: Pneumococcal polysaccharide conjugate vaccine, 13-valent adsorbed, pre-filled syringe, 0.5 mL, Prevenar 13®
Sponsor: Wyeth Australia Pty Limited
Date of PBAC Consideration: November 2010
1. Purpose of Application
The submission sought listing on the National Immunisation Program
(NIP) as a single catch up dose for children under 3 years of age
who have completed primary vaccination with 7-valent pneumococcal
conjugate vaccine (7vPCV).
7-valent pneumococcal conjugate vaccine (Prevenar®) has been available under the NIP since 1 January 2005. The vaccine is administered
at two, four and six months of age, with a fourth dose at 12 months of age for medically
at risk children and a booster dose of 23-valent pneumococcal polysaccharide vaccine
(23vPPV) at 4 years of age.
At the July 2010 PBAC meeting, the Committee recommended listing on the NIP of 13-valent pneumococcal conjugate vaccine (13vPCV, Prevenar 13®) under the same circumstances of use as the existing NIP listed 7vPCV. A Public Summary Document is available.
3. Registration Status
13vPCV was TGA registered on 29 March 2010 for active immunisation
for the prevention of disease caused by Streptococcus
pneumoniae serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A,
19F and 23F (including invasive disease, pneumonia and acute otitis
media) in infants and children from 6 weeks up to 5 years of age.
The use of 13vPCV should be determined by official recommendations,
taking into consideration the impact of invasive pneumococcal
disease in different age groups as well as variability of serotype
epidemiology in different geographical areas.
4. Listing Requested and PBAC’s View
The submission requested inclusion of 13vPCV on the NIP as a single
supplementary dose (catch up) for those children under 3 years of
age who have completed primary vaccination with 7vPCV.
For PBAC’s view, see Recommendations and Reasons.
5. Clinical Place for the Proposed Therapy
S. pneumoniae is a bacterial pathogen responsible for
invasive pneumococcal disease (IPD) such as bacteraemia and
meningitis and non-invasive pneumococcal disease (non-IPD) such as
pneumonia, acute otitis media and sinusitis depending on the site
of infection. IPD is a major cause of morbidity and mortality
particularly in children aged less than 2 years, with a 20 %
case-fatality rate for pneumococcal meningitis. IPD caused by
serotypes not covered by the currently available vaccines,
predominantly 19A, have been increasing.
Currently, childhood immunisation against diseases caused by S. pneumoniae can be achieved by either vaccinating with 7vPCV, 10-valent protein D pneumococcal conjugate vaccine (10vPDPCV) or 23vPPV (for Aboriginal and Torres Strait Islander children in high risk areas at 18 – 24 months and for medically at-risk children as a booster at 4 years of age). The 13vPCV catch up program proposed by this submission will provide additional serotype coverage to children who have completed primary vaccination with 7vPCV only.
The submission nominated a primary vaccination series with 7vPCV
(i.e. ‘no catch up dose’) as the main comparator. The
PBAC considered this appropriate.
7. Clinical Trials
The submission presented one randomised trial (Study 008) comparing
7vPCV primary series followed by 13vPCV booster (catch-up) dose
with either 7vPCV primary series followed by 7vPCV booster
(catch-up) dose or 13vPCV primary series followed by 13vPCV booster
(catch-up) dose in healthy infants. The submission also presented
one supporting non-randomised study (Study 3011) of a 13vPCV
booster (catch-up) dose in healthy infants aged 1 to 9 years who
have received at least three doses of 7vPCV.
None of these trials had been published at the time of submission.
8. Results of Trials
Comparative efficacy was assessed based on two key comparisons
using data from Study 008:
Main comparison: Whether a 13vPCV booster dose produced an immune response to the six additional serotypes that was greater than that achieved with a 3-dose 7vPCV primary series.
Benchmark comparison: Whether a 13vPCV booster dose produced an immune response to the six additional serotypes that is similar to that achieved with a 3-dose 13vPCV primary series.
The following data from Study 008 were used to support the main comparison:
Comparison 1: 7vPCV primary series (measured pre-toddler) versus 7vPCV primary series plus 13vPCV (measured post-toddler dose). Immunological measures: IgG responders (percentage of subjects with pneumococcal antibody concentrations of ≥ 0.35 micrograms/mL) and IgG mean geometric concentration (GMC).
The following data from Study 008 were used to support the benchmark comparison:
Comparison 2: 13vPCV primary series (measured post-primary series) versus 7vPCV primary series plus 13vPCV (measured post-toddler). Immunological measures: IgG responders and IgG GMCs
Comparison 3: 13vPCV primary series plus 13vPCV (measured post-toddler) versus 7vPCV primary series plus 13vPCV (measured post-toddler). Immunological measures: opsonophagocytic assay (OPA) responder rates (proportion achieving an antibody titre of ≥ 1:8) and mean geometric titre (GMT).
As supportive evidence the submission also presented OPA responder data for 7vPCV based on pooled data which compared a 7vPCV primary series to 13vPCV primary series (presented in the previous submission for the 13vPCV primary series).
One comparison using data from the supportive non-randomised Study 3011 was presented as supportive evidence of efficacy of a booster (catch-up) dose of 13vPCV in older children ≥ 2 to < 5 years who were previously vaccinated with up to four doses of 7vPCV. This was demonstrated by comparing immunogenicity response pre-dose of 13vPCV compared to post-dose measured using IgG responders.
Immunological response rates pre-toddler dose ranged from 2.6% to 79.5%, increasing to 89.9% to 100% after the 13vPCV toddler dose. The 95% confidence intervals did not overlap for any serotype.
For 13vPCV post-primary series, immunological response rates ranged from 84.0% to 97.5%, and in the 7vPCV/13vPCV post toddler dose group, response rates ranged from 89.9% to 100%. The submission claimed that the overlapping 95% confidence intervals suggested that for each serotype, the proportions of responders were the same or higher in the 7vPCV/13vPCV group and that there was no statistically significant difference between the two groups.
The proportion of OPA responders in the 13vPCV/13vPCV group ranged from 98.8% to 100% versus 97.8% to 100% in the 7vPCV/13vPCV group. The 95% confidence intervals overlapped for every serotype. The submission suggested that the results are similar and that it could be inferred that children previously vaccinated with 7vPCV (primary series) and receiving a single dose of 13vPCV (booster) achieve similar levels of functional antibodies compared to those who receive four doses of 13vPCV, for the six additional serotypes.
Supportive comparisons (to previous data)
The submission presented data on subjects achieving an OPA antibody titre ≥ 1:8 for 7vPCV post-primary series versus 7vPCV/13vPCV post toddler dose for the evaluable immunogenicity population. The proportion of OPA responders in the 7vPCV post-primary series group ranged from 7.0% to 71.0% versus 97.8% to 100% in the 7vPCV/13vPCV group.
The submission also presented data on IgG responders pre-study dose versus post-study dose with 13vPCV for the evaluable immunogenicity population in older children previously vaccinated with up to four doses of 7vPCV. The percentage of IgG responders before vaccination ranged from 12.7% to 97.7%. After a single dose of 13vPCV, the proportion of responders increased, ranging from 92% to 100%. The 95% confidence intervals overlapped for one of the six additional serotypes.
The safety analysis presented was based on Study 008 and Study 3011, with a total of 1041 infants vaccinated. The safety analyses demonstrated that there was a higher rate of reported local reactions, systemic events and adverse events with 13vPCV booster (catch-up) dose compared to no 13vPCV booster (catch-up) dose during the toddler dose interval. There were no deaths recorded. The submission did not undertake an extended assessment of comparative harms.
9. Clinical Claim
The submission claimed that a 7vPCV primary series followed by a
booster (catch-up) dose of 13vPCV is superior in terms of
comparative effectiveness over 7vPCV primary series only for the
six additional serotypes.
The PBAC considered the advice of the Australian Technical Advisory Group on Immunisation (ATAGI) and was satisfied that there are likely to be some incremental direct benefits of a catch-up program concurrent with the use of 13vPCV in the infant pneumococcal program. See Recommendation and Reasons.
10. Economic Analysis
A stepped economic evaluation was presented. A decision analytic
model was used to estimate the number of cases and deaths from IPD
(meningitis or bacteraemia), inpatient and outpatient-treated
community acquired pneumonia (all-cause), and simple and complex
otitis media (all-cause) caused by the additional six serotypes
included in the 13vPCV compared with 7vPCV.
The incremental cost-effectiveness ratio (ICER) for the re-specified base case was calculated to be in the range of $15,000 - $45,000. For the younger cohort of patients aged between 12-23 months, the ICER was also in the range of $15,000 - $45,000. For the older cohort of patients aged 24-35 months, the ICER was in the range of $45,000 - $75,000.
11. Estimated PBS Usage and Financial Implications
The likely number of patients was estimated by the submission to be
over 200,000 in 2011. The financial cost to the NIP was estimated
to be in the range of $10 – 30 million in 2011.
For PBAC’s view, see Recommendation and Reasons.
12. Recommendations and Reasons
The PBAC recommended extension of the recommended listing, in the
NIP, of 13vPCV to include a single supplementary (catch-up) dose of
13vPCV for children aged between 12 and 23 months who have
completed primary vaccination with 3 doses of 7vPCV, assuming that
the catch-up program commences at around the same time as any
switch from 7vPCV to 13vPCV on the NIP. Although noting that some
uncertainty remained about the duration of direct benefits and the
extrapolation of the surrogate immunogenicity data provided into
clinical benefits, the Committee considered that the ICER of
between $15,000 - $45,000 per quality adjusted life-year (QALY)
using the QALY weights proposed during the evaluation, including
direct and indirect effects and the current price of 13vPCV,
represented acceptable cost-effectiveness in this context.
The Committee however did not recommend that the catch-up program for 13vPCV include the requested cohort of children aged from 24 to 35 months, because it considered that the ICER for this cohort was unacceptably high. Additionally, the submission may not have captured all the costs associated with administering the 13vPCV to this older cohort for whom there is no scheduled NIP vaccination point. However, the PBAC indicated that should the ICER be reduced so that it was similar to that for the 12 – 23 month cohort, it would be prepared to consider, out-of-session, amending its recommendation to include the older age group.
In making these recommendations, the Committee acknowledged the ATAGI advice that since the introduction of 7vPCV, the majority of IPD in non-indigenous children has been caused by serotypes contained in 13vPCV but not in 7vPCV. Furthermore, since 2005 there has been a progressive increase in the number of IPD cases caused by some of these serotypes, most notably serotype 19A. Approximately twice as many cases of IPD caused by 13v-non-7vPCV serotypes occur among children aged 12 – 23 months compared with those aged 24 – 35 months, so more favourable cost-effectiveness would be expected from a catch up program targeting those aged 12 – 23 months.
Acceptance of the submission’s efficacy claim for a 13vPCV catch-up program rested upon accepting that the surrogate immunogenicity data provided for 13vPCV translated into clinically important outcomes, but the ATAGI advice was that this was likely. The Committee was satisfied by ATAGI’s advice that there are likely to be some incremental direct benefits of a catch-up program concurrent with the use of 13vPCV in the infant pneumococcal program. These will be most readily measurable as a reduction in cases of IPD caused by 13v-non7v serotypes, in particular serotype 19A. The PBAC agreed that the use of the utility values from Prosser (2004) in the economic model was inappropriate. The Committee considered that the alternative utility values proposed in the evaluation, although somewhat conservative against 13vPCV, provided the most appropriate basis for a listing recommendation.
The Committee also noted that the duration of effect of the vaccine was uncertain and that if it is less than the 5 years assumed by the economic model, the ICER will become less favourable. However, the PBAC considered that the approach taken by the sponsor in calculating the base case ICER was reasonable.
Lastly, the PBAC acknowledged that the overall cost to the NIP of implementing a catch-up program for 13vPCV, is both high and uncertain and likely to exceed $10 million even if restricted to children aged between 12 and 23 months.
Further out-of-session PBAC consideration:
Subsequent to receiving the PBAC recommendations for the 13vPCV
catch-up immunisation, the sponsor resubmitted the economic model
so that the ICER for the cohort of children aged from 24 to 35
months was also in the range of $15,000 - $45,000 per QALY.
Based upon this proposal, the PBAC amended its previous recommendation to recommend out-of-session to the Minister the extension of the recommended listing, in the NIP, of 13vPCV to include a single supplementary (catch-up) dose of 13vPCV for children aged between 12 and 35 months who have completed primary vaccination with 3 doses of 7vPCV, assuming that the catch-up program commences at around the same time as any switch from 7vPCV to 13vPCV on the NIP.
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
Wyeth is pleased that a catch-up program for Prevenar 13 will be
available on the National Immunisation Program for children who
have completed primary vaccination with Prevenar. This will provide
protection against the additional serotypes covered by Prevenar 13,
particularly serotype 19A, which the sponsor believes is
responsible for the greatest burden of invasive pneumococcal
disease in Australia.