Adefovir Dipivoxil, tablet, 10 mg, Hepsera®, March 2007
Public summary document for Adefovir Dipivoxil, tablet, 10 mg, Hepsera®, March 2007
Page last updated: 29 June 2007
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Public Summary Document
Product: Adefovir Dipivoxil, tablet, 10 mg,
Hepsera®
Sponsor: Gilead Sciences Pty Ltd
Date of PBAC Consideration: March 2007
1. Purpose of Application
The resubmission requested an extension of the current Section 100
(Highly Specialised Drug) listing for patients with active chronic
hepatitis B to include the treatment in combination with lamivudine
of patients with advanced liver disease (evidence of cirrhosis on
liver biopsy or a Child Pugh Turcotte score greater than 5) or
after a liver transplant.
2. Background
The PBAC recommended listing for the second-line treatment of
chronic hepatitis B on the basis of high but acceptable
cost-effectiveness compared with on-going ‘failed’
lamivudine therapy (100 mg daily) at the July 2004 meeting. The
Committee noted that there was a clinical need for this drug for
patients who had failed therapy with lamivudine. The PBAC concluded
that, on the balance of probabilities, adefovir would remain
acceptably cost-effective within the relatively small second-line
population with the greatest clinical need.
At its July 2006 meeting the PBAC considered a submission to extend
the Section 100 (Highly Specialised Drug) listing for patients with
active chronic hepatitis B to include the treatment in combination
with lamivudine of nucleoside therapy naïve patients with
advanced liver disease, and liver transplant patients with a
history of hepatitis B virus (HBV) infection.
The PBAC rejected the submission because the patients in the
pivotal clinical trial did not reflect the population requested in
the restriction, the comparator in the key clinical trial was not
relevant to the current PBS treatment algorithm, and the
uncertainty between antiviral resistance and longer-term clinical
outcomes. These problems led to uncertainty about the clinical
claim and in the economic model.
3. Registration Status
Adefovir dipivoxil tablet 10 mg was registered on 16 September 2003
by the TGA for the treatment of chronic hepatitis B in adults with
evidence of active viral replication and either evidence of
persistent elevations in serum aminotransferases or histologically
active disease.
4. Listing Requested and PBAC’s View
Private Hospital Authority Required
Patients with chronic hepatitis B who satisfy the following
criteria:
- Active chronic hepatitis B (HBe antigen positive and/or serum HBV DNA positive) with advanced liver disease (either evidence of cirrhosis on liver biopsy or a Child Pugh Turcotte score greater than 5), adefovir may be used in combination with lamivudine.
- Active chronic hepatitis B (HBe antigen positive and/or serum HBV DNA positive) in patients who are failing antihepadnaviral therapy as demonstrated by repeatedly elevated (greater than 1.2 times the upper limit of normal) serum ALT levels. Patients must have received concurrent antihepadnaviral therapy of greater than or equal to 6 months. Patients may receive PBS subsidised treatment of lamivudine in combination with adefovir for the initial 3 months only of PBS subsidised adefovir, unless patients have advanced liver disease (evidence of cirrhosis on liver biopsy or a Child Pugh Turcotte score greater than 5), in which case adefovir may be used in combination with lamivudine.
- Patients with a prior history of liver transplant for chronic hepatitis B. Adefovir may be used in combination with lamivudine.
- Female patients of childbearing age are not pregnant, not breastfeeding, and are using an effective form of contraception.
NOTE
Patients should have undergone a liver biopsy at some point since
initial diagnosis to obtain histological evidence of chronic
hepatitis.
See Recommendation and Reasons for the PBAC’s
view
5. Clinical Place for the Proposed Therapy
To allow for combination use with lamivudine in patients with
chronic hepatitis B with advanced liver disease or with a prior
liver transplant.
6. Comparator
The comparator was unchanged from the July 2006 submission i.e.
lamivudine monotherapy followed by adefovir dipivoxil monotherapy
as the main comparator for patients with lamivudine-sensitive HBV
(treatment-naïve; treatment-experienced/lamivudine-sensitive;
post-transplant/lamivudine sensitive) and adefovir dipivoxil
monotherapy for patients with lamivudine-resistant HBV
(treatment-experienced/lamivudine-resistant;
post-transplant/lamivudine resistant).
7. Clinical Trials
No changes were made to the trial data presented in the previous submission. Please
see the Public Summary Document on Adefovir Dipivoxil from the July 2006 PBAC meeting.
8. Results of Trials
The re-submission provided new information to: (i) support the
claim that the development of resistance in CHB patients with
cirrhosis or post-liver transplant leads to clinically meaningful
outcomes; (ii) support emerging data which suggests that the
resistance rates for adefovir given sequentially in lamivudine
resistant patients are higher than for treatment naïve
patients given adefovir; and (iii) lower rates of resistance
develop to lamivudine and adefovir when given concomitantly
compared with sequential lamivudine and adefovir treatment.
9. Clinical Claim
The submission claimed that adefovir dipivoxil plus lamivudine
combination therapy has significant advantages in effectiveness
over the main comparator and is associated with similar or less
toxicity.
See Recommendation and Reasons for PBAC’s
views.
10. Economic Analysis
An updated preliminary economic evaluation was presented. The
choice of the cost-effectiveness approach was valid. The variables
included in the evaluation were the cost of adefovir, the cost of
lamivudine and the proportion of patients that develop antiviral
resistance.
The trial-based incremental discounted cost per extra patient
avoiding lamivudine resistance was between $45,000 – 75,000
in Year 2.
The trial-based incremental discounted cost per extra patient
avoiding adefovir resistance was between $105,000 – 200,000
in Year 2 and $34,079 in Year 4.
An updated modelled economic evaluation was presented. The base
case modelled incremental discounted cost per extra patient with
discounted dual resistance avoided was between $15,000- 45,000. The
base case modelled incremental discounted cost per extra
patient-year of discounted dual resistance avoided: <$15,000.
The base case modelled incremental discounted cost per extra
discounted life year gained was between $45,000 –
75,000.
11. Estimated PBS Usage and Financial Implications
The likely number of prescriptions per year was a total of 10,000
– 15,000 lamivudine prescriptions and < 10,000 adefovir
prescriptions in Year 4, while the financial cost per year to the
PBS was <$10 million in year 4 assuming all cirrhotic patients
commence adefovir and lamivudine combination therapy when the
current listing is revised.
12. Recommendation and Reasons
The PBAC agreed that entecavir is a potentially competing drug with
adefovir and lamivudine combination, and comparison of the
combination treatment with entecavir should have been
presented.
The PBAC noted that while no changes had been made to the trial
data presented in the previous submission (July 2006 PBAC meeting)
new information had been provided to: (i) support the claim that
the development of resistance in CHB patients with cirrhosis or
post-liver transplant leads to clinically meaningful outcomes; (ii)
support emerging data which suggests that the resistance rates for
adefovir given sequentially in lamivudine resistant patients are
higher than for treatment naïve patients given adefovir; and
(iii) lower rates of resistance develop to lamivudine and adefovir
when given concomitantly compared with sequential lamivudine and
adefovir treatment.
The PBAC agreed that it is clinically important that treatments be
made available to prevent the development of resistance to
antiviral medications. The PBAC also noted from the hearing that
there was a clinical need for combination therapy to be made
available to high risk patients. However, the new data presented
did not assist the PBAC in forming a view about the cost
effectiveness of combination therapy. The results were difficult to
critically appraise given the lack of control, lack of blinding,
possible confounding variables and selection bias inherent in the
study designs.
The PBAC considered, on the available information, it had not yet
been validated that the HIV treatment model of combination
treatment, although plausible, should be the preferred approach for
the treatment of hepatitis B in terms of cost-effectiveness.
The updated modelled economic evaluation applied the resistance
rates and transition probabilities presented in earlier
submissions. The PBAC noted the ESC advice with respect to
uncertainties associated with the model, including the relevance of
the model population to the population for whom PBS listing was
sought.
Therefore, the PBAC rejected the application because of a lack of
uncertain clinical effect and uncertain cost-effectiveness in the
population for whom listing was requested.
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
The Sponsor disagrees with the PBAC opinion regarding clinical effectiveness of combination therapy in the context of drug resistant hepatitis B. The Sponsor however wishes to continue working with the PBAC to overcome issues of uncertainty regarding cost-effectiveness of combination therapy in patients with advanced liver disease and the post liver transplant patient population to achieve a PBS listing for combination therapy.