Quadrivalent human papillomavirus (Types 6, 11, 16, 18) recombinant vaccine, solution for injection, 0.5 mL, solution for injection pre-filled syringe single dose, Gardasil® - November 2011
Page last updated: 02 March 2012
Public Summary Document
Product: Quadrivalent human papillomavirus (Types
6, 11, 16, 18) recombinant vaccine, solution for injection, 0.5 mL,
solution for injection pre-filled syringe single dose,
Gardasil®
Sponsor: CSL Limited
Date of PBAC Consideration: November 2011
1. Purpose of Application
To seek an extension of the current listing on the National
Immunisation Program (NIP) to include prevention of human
papillomavirus (HPV) in males 12-13 years of age and a catch-up
program over 2 years for Year 9 males.
2. Background
At the March 2011 meeting, the PBAC rejected a request to extend
the NIP listing for Gardasil to include the prevention of HPV in
males 12 to 13 years of age and a catch-up program over 2 years for
Year 9 males because of unacceptably high and uncertain
cost-effectiveness. This conclusion was reached despite a
substantially lower proposed price because of insufficient evidence
to demonstrate the claimed effects of the vaccine in reducing the
rate of future HPV-associated cancers beyond the previously
accepted effects on cervical cancer.
For further details refer to March 2011 Public Summary
Document.
3. Registration Status
Gardasil was first registered on 22 June 2006 and is currently registered by the TGA for the following indications:
- Prevention of cervical, vulvar, vaginal and anal cancer, precancerous or dysplastic lesions, genital warts and infection caused by HPV types 6, 11, 16 and 18 (which are included in the vaccine) in females aged 9 to 45 years* ; and
- Prevention of anal cancer, precancerous or dysplastic lesions, external genital lesions and infection caused by HPV types 6, 11, 16 and 18 (which are included in the vaccine) in males aged 9 to 26 years.
*Immunogenicity studies have been conducted to link efficacy in
females and males aged 16 to 26 years to the younger
populations.
4. Listing Requested and PBAC’s View
The requested listing was unchanged, refer to March 2011 Public
Summary Document.
5. Clinical Place for the Proposed Therapy
Refer to March 2011 Public Summary Document.
6. Comparator
The resubmission did not explicitly state the primary
comparator.
The results of the revised economic evaluation were presented in
terms of the secondary comparator from the previous submission
(current female HPV vaccination).
7. Clinical Trials
The re-submission presented an alternative analysis of the same
trial data (Protocol 020) in the men who have sex with men (MSM)
sub-group and prospective studies to support the claim of a link
between anal intraepithelial neoplasia (AIN) and anal cancer.
8. Results of Trials
The submission presented efficacy results regarding the number of
external genital lesions (EGLs) in the per-protocol efficacy
population (PPE), generally HPV naive population (GHN), FAS (Full
analysis set) and HNRT (Naïve to the Relevant-HPV-type)
populations. Overall, the vaccine efficacy against HPV 6,11,16,18
related EGL in the PPE population was 90.6% (95% CI: 70.1 –
98.2).
The alternative analysis of efficacy against AIN in the MSM sub
population in Protocol 020 included some cases of AIN which were
re-assigned to non-vaccine HPV types. The reassignment resulted in
increased estimates of the efficacy of the vaccine. The data
highlight the sensitivity of the results of vaccine efficacy with
respect to how cases are assigned as related to HPV 6, 11, 16 or
18. Overall, the vaccine efficacy against HPV 6, 11, 16, 18 related
AIN any grade in the PPE population was 77.5% (95% CI: 39.6 –
93.3) in the original analysis and 91.1% (95% CI: 64.2 –
99.0) in the re-assigned cases analysis.
The re-submission presented further evidence to support the claim
that the results for the MSM sub-group of protocol 020 can be
generalised to the general male population (the proposed NIP
population).
For PBAC’s view on these results, see Recommendation and
Reasons.
The re-submission presented new toxicity data, in terms of
additional analyses of serious injection site reactions in
Protocols 016, 018 and 020. The data from Protocol 020 indicated
that most injection site reactions were judged to be of mild or
moderate intensity, but severe injection site adverse events were
reported by 2% (60 of 3003 subjects followed up for 5 days after
any injection):
- 0.8% (25/3003) reported severe pain
- 0.8% (25/3003) reported severe swelling (>2 inches)
- 0.8% (23/3003) reported severe erythema (>2 inches).
9. Clinical Claim
The clinical claim in the March 2011 submission described GARDASIL
as being therapeutically superior and having significant clinical
advantages with greater toxicity than the main comparator, placebo.
The PBAC previously accepted this claim regarding the use of the
GARDASIL in adolescent and young adult males in a universal
program.
The PBAC considered that the claim of a vaccine treatment effect on
oropharyngeal (HPVOP) cancer was only weakly supported by the
evidence presented in the re-submission. The PBAC noted that only
HPV serotype 16 is associated with this form of cancer, the
attributable fraction of oropharyngeal cancer due to HPV serotype
16 compared to other factors such as smoking and HIV infection is
not clear and there is no evidence of any difference in
oropharyngeal HPV infections or cancer precursers between
vaccinated and unvaccinated populations.
10. Economic Analysis
An updated modelled economic evaluation was presented of the
male+female vaccination program vs female vaccination only.
The model was a hybrid model, as previously, which comprised a
Dynamic Infectious Disease Model and a Markov model.
The results of the economic evaluation produced a base case ICER of
between $15,000 - $45,000/QALY.
The vaccine coverage for males was reduced by 10 % from the
previous submission to a first dose coverage of 70 %, the catch-up
program was included and the price was reduced.
The PBAC considered the removal of penile and perineal cancers from
the economic evaluation appropriate given that the available data
were insufficient to support a claim of a vaccine treatment effect
on these types of cancer. The PBAC noted that HPVOP cancer remained
in the economic evaluation, however, vaccine efficacy against HPVOP
cancer was assumed to be between 0 % and 100 % of AIN vaccine
efficacy (whereas previously it was 100 %).
The incidences of anal and HPVOP cancers were assumed to grow
indefinitely into the future based on a multiplicative rather than
an additive model and the ICER was highly sensitive to whether the
incidence of anal and HPVOP cancers was assumed to grow
indefinitely. When no growth of anal cancer and HPVOP cancer is
assumed after 2014, the PBAC noted that the ICER increases to
between $45,000 - $75,000/QALY.
Sensitivity analyses were conducted on both the Dynamic Infectious
Disease model and Markov model.
The ICER was sensitive to vaccine efficacy against HPVOP and anal
cancer in the Markov model (based on comparing the ICER assuming
the upper and lower 95% confidence intervals for vaccine efficacy
based on the GHN population). The ICER was also sensitive to the
cost of administration, the incidence of genital warts, the
proportion of the population who were MSM, and the proportion of
anal cancers attributable to HPV 16/18. The ICER was largely
insensitive to changes in the other parameters.
11. Estimated PBS Usage and Financial Implications
The likely number of patients/year was estimated by the submission
to be greater than 200,000 in Year 1, consisting of 12 year old
males, 12-year old females (who are already immunised under the
existing GARDASIL programme), and 14-year old males under the
proposed catch-up programme (which runs for the two years following
listing).
The financial cost/year to the NIP was estimated by the submission
to be between $5 – $30 million in Year 1.
12. Recommendation and Reasons
The PBAC recommended extension of the National Immunisation Program
listing of quadrivalent human papillomavirus (HPV) (types 6, 11,
16, 18) recombinant vaccine, solution for injection 0.5 mL, to
include ongoing administration to males approximately twelve to
thirteen years of age in a school-based program and for two
catch-up cohorts for all males in the two year groups above the
ongoing cohort, delivered over two years for Year 9 males, on the
basis of acceptable cost effectiveness compared with female-only
vaccination, which forms the basis of the revised economic
evaluation in the re-submission.
The PBAC noted that no direct evidence was presented regarding HPV
vaccine efficacy against anal or other cancers. The re-submission
presented an alternative analysis of the same trial data (Protocol
020) in the men who have sex with men (MSM) sub-group and
prospective studies to support the claim of a link between anal
intraepithelial neoplasia (AIN) and anal cancer. The PBAC also
noted the additional studies identified by ATAGI including Watson
2006 regarding the postulated link between AIN and anal cancer. The
PBAC considered that quantifying the risk of progression to anal
cancer from AIN remained uncertain, and that detecting and staging
AIN was less consistent than has already been accepted with
cervical intraepithelial neoplasia. However, on balance, that the
evidence supported some association between AIN and progression to
anal cancer, in particular for higher grade AIN (AIN-2 and AIN-3).
The PBAC considered that uncertainty remained about the magnitude
of the association between AIN and progression to anal cancer, the
extent to which AIN and anal cancers are associated with HPV
serotypes 16 and 18 compared with other strains of HPV, and the
influence of other risk factors on the causal pathway to anal
cancer.
The re-submission presented further evidence to support the claim
that the results for the MSM sub-group of protocol 020 can be
generalised to the general male population (the proposed NIP
population). The PBAC noted the ATAGI advice and considered that,
based on the available evidence, the development of HPV-related AIN
and anal cancer are likely to be similar in nature across the MSM
and the general male populations and hence that HPV vaccine
efficacy is likely to be similar in relative terms across these
populations. The PBAC noted it had previously accepted HPV vaccine
efficacy against condyloma acuminata (genital warts) in females and
males attributable to HP 6 or 11 and AIN in the MSM sub-group
attributable to HPV 16 or 18.
The PBAC noted that an updated economic evaluation was presented.
The PBAC considered the removal of penile and perineal cancers from
the economic evaluation appropriate given that the available data
are insufficient to support a claim of a vaccine treatment effect
on these types of cancer. The PBAC also considered that the claim
of a vaccine treatment effect on oropharyngeal (HPVOP) cancer was
only weakly supported by the evidence presented in the submission,
noting that only HPV serotype 16 is associated with this form of
cancer, the attributable fraction of oropharyngeal cancer due to
HPV serotype 16 compared to other factors such as smoking and HIV
infection is not clear and there is no evidence of any difference
in oropharyngeal HPV infections or cancer precursors between
vaccinated and unvaccinated populations. The PBAC noted that
although HPVOP cancer remained in the economic evaluation, vaccine
efficacy against HPVOP cancer was assumed to be between 0 % and 100
% of AIN vaccine efficacy (whereas previously it was 100 %). The
PBAC did not accept the sponsor’s base case (percentage of
vaccine efficacy against HPVOP set to 100 % of AIN vaccine
efficacy), but did accept that, where the percent of vaccine
efficacy against HPVOP is set to zero, this preferred base case
would not include any reduction in HPVOP. The PBAC therefore
accepted a base case ICER of between $15,000 - $45,000/QALY
(varying depending on whether the 95 % or 99 % lower bound of the
confidence interval of the annual percentage change in the
incidence of anal and HPVOP cancers is used in the model). The PBAC
noted that there were likely to be other oncogenes against which
future vaccines could be targeted, which conflicts with any
acceptance of the claimed 100 % of AIN vaccine efficacy.
The vaccine coverage for males was reduced by 10 % from the
previous submission to a first dose coverage of 70 %, which the
PBAC considered was reasonable. The PBAC also noted that the
catch-up program was included in the economic evaluation in the
re-submission and that the price was reduced from the previous
submission.
The incidence of both anal and HPVOP cancers was assumed to grow
indefinitely into the future based on a multiplicative rather than
an additive model and the PBAC considered both assumptions to be
improbable. The PBAC also noted that the ICER was highly sensitive
to whether the incidence of anal and HPVOP cancers is assumed to
grow indefinitely. When no growth of anal cancer and HPVOP cancer
is assumed after 2014, the PBAC noted that the ICER increases to
between $45,000 – $75,000/QALY.
The PBAC considered the assumed lifetime efficacy of HPV vaccine in
the economic evaluation to be uncertain and noted the ATAGI advice
that the clinical relevance of waning of antibodies to HPV 18
remains unknown.
The PBAC noted that the sponsor proposed a price weighted by gender
uptake, with the price adjusted based on actual uptake. The PBAC
recommended that the weighted price be based on the eligible
population rather than the existing female HPV vaccine register
population, as the register was set-up specifically to monitor the
female HPV vaccination program and to allow assessment of HPV
vaccine effectiveness in preventing cervical abnormalities and
cervical cancer.
The PBAC recommended that a register of males who are vaccinated,
similar to that implemented for the female program, should be
established and maintained. The register would need to have the
capacity to identify and recall adolescents who have had an
incomplete vaccination course or to receive a booster dose in the
event that a booster dose is required. In addition, sentinel HPV
type surveillance should be established and maintained to detect
HPV genotypes causing anal, oropharyngeal, penile and perineal
cancers. The PBAC noted that the vaccine sponsor had financially
supported a register and sentinel surveillance program for funded
use of the vaccine by girls, and advised that this support should
extend to cover funded use of the vaccine by boys. Similarly, the
PBAC noted that the vaccine sponsor had provided financial and
“in kind” support for the promotion of a successful
delivery of a complete 3-dose program, including for the
recruitment and training of immunisation providers and the
development of educational materials.
In making this recommendation the PBAC noted the consumer comments
on this item.
Recommendation:
To extend beyond the cohorts in the current NIP program for females
as follows:
- Ongoing cohort of males approximately 12 – 13 years of age in a school-based program. This cohort to be consistent with the current school-based HPV vaccine program for females.
- Two catch-up cohorts for all males in the two year groups above the ongoing cohort – delivered as a catch-up program over two years for Year 9 males.
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
CSL welcomes the PBAC decision to recommend the extension of the National Immunisation Program listing of the quadrivalent HPV (types 6, 11, 16, 18) vaccine to include males.
