Telbivudine, tablet, 600 mg, Sebivo, March 2008
Public summary document, March 2008
Page last updated: 04 July 2008
Public Summary Documents
Product: Telbivudine, tablet, 600 mg, Sebivo
Sponsor: Novartis Pharmaceuticals Australia Pty Ltd
Date of PBAC Consideration: March 2008
1. Purpose of Application
The application sought a Section 100 (Highly Specialised Drug) Private hospital authority
required listing for patients with chronic hepatitis B who are nucleoside analogue
naїve and who satisfy certain criteria.
Highly Specialised Drugs are medicines for the treatment of chronic conditions, which,
because of their clinical use or other special features, are restricted to supply
to public and private hospitals having access to appropriate specialist facilities.
2. Background
At the July 2007 meeting, the PBAC rejected a submission for telbivudine, which sought
a section 100 (Highly Specialised Drug) listing for the treatment of patients with
chronic hepatitis B, based on uncertainty about the cost effectiveness over lamivudine
and uncertainty about the claim of similar safety and efficacy in comparison with
entecavir.
At the November 2007 meeting the PBAC agreed that testing for hepatitis B could be
carried out by serum HBV DNA testing for chronic hepatitis B patients, however it
was not certain if funding under Medicare had been finalised at the time of the March
2008 meeting.
3. Registration Status
Telbivudine was registered by the TGA on 5 March 2007 and is indicated for the treatment of HBe-Ag-positive and HBeAg-negative chronic hepatitis B in patients who have compensated liver disease, evidence of viral replication and active liver inflammation and who are nucleoside analogue naﶥ.
4. Listing Requested and PBAC’s View
Section 100 (Highly Specialised Drugs Program)
Private hospital authority required
Patients aged 16 years or older with chronic hepatitis B who are nucleoside analogue
naﶥ and satisfy all of the following criteria:
(1) Histological evidence of chronic hepatitis on liver biopsy (except in patients
with coagulation disorders considered severe enough to prevent liver biopsy);
(2) Abnormal serum ALT levels in conjunction with documented chronic hepatitis B infection
(HBe antigen positive and/or HBV DNA positive);
(3) Female patients of child-bearing age are not pregnant, not breast-feeding, and
are using an effective form of contraception.
Persons with Child's class B or C cirrhosis (ascites, variceal bleeding, encephalopathy,
albumin less than 30 g per L, bilirubin greater than 30 micromoles per L) should have
their treatment discussed with a transplant unit prior to initiating therapy.
NOTE:
PBS-subsidised telbivudine must be used as monotherapy.
For PBAC’s view see Recommendation and Reasons.
5. Clinical Place for the Proposed Therapy
Telbivudine would provide an alternative first-line oral treatment for chronic hepatitis B (CHB).
6. Comparator
The submission nominated lamivudine and entecavir as the main comparators. These were accepted by the PBAC as appropriate.
7. Clinical Trials
The re-submission provided an update of its search strategy. No additional trials were located by the updated search. The following trials were included in this submission:
- two direct randomised comparative trials comparing telbivudine 600 mg and lamivudine 100 mg in HBeAg-positive and HBeAg-negative patients with CHB and compensated liver disease, over 104 weeks (trial NV-02B-007 and trial NV-02B-015);
- one pooled unweighted analysis of data from the subgroup of Chinese patients in trial NV-02B-007 with data from patients (all Chinese) in trial NV-02B-015; and
- two randomised comparative trials of entecavir 0.5 mg versus lamivudine 100 mg in HBeAg-positive and HBeAg-negative CHB patients with compensated liver disease, each of 52 weeks duration (Chang et al, 2006 and Lai et al, 2006).
Details of the trials published at the time of the submission are available in the
July 2007 Public Summary Document.
8. Results of Trials
Trial NV-02B-007
The PBAC previously considered that there were statistically significant differences
in the proportion of HBeAg-positive subjects with therapeutic response at Week 52
(primary endpoint) and Weeks 76 and 104 for telbivudine 600 mg versus lamivudine 100
mg in trial NV-02B-007. However, the Committee considered it was unlikely that the
difference in therapeutic response reported at Week 52 (primary endpoint) is clinically
important because the statistical analysis plan implies that a difference of 15% is
the minimum clinically important difference (the non-inferiority margin calculated
for this outcome was -15%). Clinically important differences were reported at Weeks
76 and 104.
The PBAC previously considered that there was a statistically significant advantage
for telbivudine treatment compared with lamivudine treatment in the proportion of
HBeAg-negative subjects with therapeutic response at Week 104, but there was no statistically
significant difference at Weeks 52 (primary endpoint) and 76, in trial NV-02B-007.
The PBAC considered it is unlikely that the difference in therapeutic response reported
at Week 104 is clinically important.
Trial NV-02B-015
There were statistically significant advantages for telbivudine treatment compared
with lamivudine treatment for the primary endpoint, mean hepatitis B virus (HBV) reduction from baseline in HBeAg-positive subjects. It appeared that clinically important differences were detected for mean
HBV DNA reduction from baseline at Weeks 76 and 104, but not at Weeks 24 and 52 (non-inferiority
margin, NIM = 1.0 log10copies/mL). Clinical importance was estimated by applying the
NIM reported in the statistical analysis plan of the key trial, NV-02B-007 (information
regarding the NIMs in trial NV-02B-015 were not provided). The 95% CIs appeared to
include clinically unimportant differences.
There were statistically significant and clinically important differences in the proportion
of HBeAg-positive subjects with a therapeutic response (primary endpoint in the key
trial, NV-02B-007) at Weeks 52 and 104 for telbivudine 600 mg versus lamivudine 100
mg in trial NV-02B-015 (NIM = -15%). The 99% CIs appeared to include predominantly
clinically important differences.
There was no statistically significant difference in the primary endpoint, mean HBV DNA reduction from baseline in HBeAg-negative subjects between
telbivudine 600 mg and lamivudine 100 mg. The HBeAg-negative subgroup was not of sufficient size to detect statistically significant differences
in this endpoint (n=20 and 22), however the difference was numerically in favour of
telbivudine. It appeared that clinically important differences were detected for mean
HBV DNA reduction from baseline at Week 104, but not at Weeks 24, 52 and 76 (NIM =
1.0 log10copies/mL). The 95% CIs appeared to include clinically unimportant differences.
There was a statistically significant and clinically important difference in the proportion
of HBeAg-negative subjects with a therapeutic response (primary endpoint in the key trial, NV-02B-007)
at Week 52, but not at Week 104, for telbivudine 600 mg versus lamivudine 100mg in
trial NV-02B-015, based on the NIMs reported in the statistical analysis plan of the
key trial, NV-02B-007. The 99% CI for therapeutic response appeared to include clinically unimportant
differences.
The re-submission presented new toxicity data from trial NV-02B-015. There were similar
proportions of patients with greater than one adverse event (64.7%, 108/167 versus
60.6%, 100/165, respectively) and treatment discontinuations (1.2% versus 1.8%, respectively)
for telbivudine and lamivudine treatment. Rates of reported on-treatment adverse events
were similar between telbivudine and lamivudine except for nasopharyngitis (29.3%
versus 23.6%, respectively). Although the incidence of adverse events and the proportion
of patients with nasopharyngitis were numerically higher in the telbivudine arm versus
the lamivudine arm in trial NV-02B-015, overall telbivudine and lamivudine appeared
to have similar toxicity.
9. Clinical Claim
The re-submission described telbivudine as superior in terms of comparative effectiveness
and non-inferior in terms of comparative safety over lamivudine. Based on the supporting
data, the PBAC considered this description was reasonable for HBeAg-positive patients but was not reasonable for HBeAg-negative patients.
The data presented continue to support the conclusion that telbivudine may be non-inferior,
rather than superior, to lamivudine in HBeAg-negative patients.
The re-submission did not provide additional evidence to address the uncertainty concerning
the claim that telbivudine is no worse that entecavir in terms of efficacy and safety.
The PBAC considered based on the supporting data, this description was not reasonable.
10. Economic Analysis
An updated modelled (stepped) economic evaluation was presented. The choice of the
cost-utility approach was considered valid. The model measured lifetime healthcare
costs associated with CHB and predicted survival in quality-adjusted life years for
the HBeAg-positive and negative cohorts, and for two different treatment arms, telbivudine
and lamivudine. The number of viral load (VL) levels was reduced from five in the
original submission to two (VL<300copies/mL or VL≥300copies/mL) in the re-submission.
The model used data from an extended period (two years) of trial NV-02B-007 compared
to one year of trial data in the original submission. The model extrapolated an ongoing
treatment effect on viral load for a further two years post trial period (occurred
for a lifetime in original submission). The base-case economic evaluation was defined
using a twenty-year duration, and duration of viral load shifts of four years (two
years during the trial and extrapolation for a further two years – with an assumption
of continuing treatment effect). All transition probabilities between viral load categories
were assumed to equal zero after this period. The model was allowed to continue for
a lifetime. The model used six-monthly cycles.
For the base case modelled incremental cost per extra quality-adjusted life year (QALY),
telbivudine was claimed to be dominant (i.e. more effective and less costly) in the
HBeAg-positive patient cohort. The incremental cost per QALY in the HBeAg-negative
cohort was in the range of $15,000 to $45,000.
The PBAC considered there was some uncertainty associated with the economic modelling
for the HBeAg-positive cohort including the duration of the model (20 years). However,
the PBAC noted that while telbivudine was dominant in the 20 year base case compared
to lamivudine, the incremental cost effectiveness ratio (ICER) at 10 years also remained
acceptable though somewhat uncertain at between $15,000 and $45,000 per extra QALY
gained.
In the HBeAg-negative patient group, the PBAC also noted the ICER for the base case
(model duration 20 years) was between $15,000 and $45,000 per extra QALY gained compared
with lamivudine, and when the duration of the model was reduced to10 years the ICER
increased to greater than $200,000 and was considered unacceptably high.
11. Estimated PBS Usage and Financial Implications
The submission estimated the likely number of patients per year to be less than 5,000 in Year 5, and a net financial cost per year to the PBS of less than $5 million in Year 5.
12. Recommendation and Reasons
The PBAC recommended the listing of telbivudine for the treatment of chronic hepatitis
B in patients who are nucleoside analogue naﶥ and who are hepatitis B antigen positive
based on a high but acceptable incremental cost effectiveness ratio compared to lamivudine.
The PBAC noted the re-submission had requested listing in the nucleoside naﶥ population
only as suggested by the Committee at the July 2007 meeting, and that it had previously
accepted that superiority in efficacy over lamivudine had been demonstrated in HBeAg-positive
patients. The PBAC considered that based on the data provided in the submission lamivudine
and telbivudine appeared to have similar toxicity.
The PBAC considered there was some uncertainty associated with the economic modelling
for the HBeAg-positive cohort including the duration of the model (20 years). However,
the PBAC noted that while telbivudine was dominant in the 20 year base case compared
to lamivudine, the incremental cost effectiveness ratio at 10 years also remained
acceptable though somewhat uncertain at between $15,000 and $45,000 per extra QALY
gained.
With respect to the submission’s claim that telbivudine is non-inferior in terms of
comparative safety and efficacy compared with entecavir, the PBAC considered there
was still uncertainty about the efficacy in comparison with entecavir on some secondary
outcomes.
With respect to the comparison of telbivudine and lamivudine in HBeAg-negative patients,
the re-submission provided additional evidence for HBeAg-negative patients in trial
NV-02B-015, but as the sub-group population was small, statistically significant differences
in HBV-DNA reduction from baseline were not detected. Overall, the data presented
continue to support the conclusion that telbivudine may be non-inferior, rather than
superior, to lamivudine in HBeAg-negative patients.
In this patient group the PBAC also noted the ICER for the base case (model duration
20 years) was between $15,000 and $45,000 per extra QALY gained compared with lamivudine,
and when the duration of model was reduced to 10 years duration the ICER increased
to over $200,000.
Therefore, the PBAC rejected the listing of telbivudine for HBeAg-negative patients
based on an unacceptably high and uncertain cost-effectiveness ratio compared to lamivudine.
Recommendation
TELBIVUDINE, tablet, 600 mg.
Restriction:
Section 100 (Highly Specialised Drugs Program)
Private hospital authority required
Treatment, as sole PBS-subsidised therapy, in a patient with HBeAg-positive chronic
hepatitis B who is nucleoside analogue naﶥ and satisfies all of the following criteria:
(1) Histological evidence of chronic hepatitis on liver biopsy (except in patients
with coagulation disorders considered severe enough to prevent liver biopsy);
(2) (a) Abnormal serum ALT levels in conjunction with documented chronic hepatitis
B infection; or
(b) Elevated HBV DNA levels in conjunction with documented chronic hepatitis B infection;
and
(3) Female patients of child-bearing age are not pregnant, not breast-feeding, and
are using an effective form of contraception.
Persons with Child's class B or C cirrhosis (ascites, variceal bleeding, encephalopathy,
albumin less than 30 g per L, bilirubin greater than 30 micromoles per L) should have
their treatment discussed
with a transplant unit prior to initiating therapy.
Pack size: 28
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.
