RIBAVIRIN, tablets, 200 mg, (112 tablets, 140 tablets and 168 tablets) and PEGINTERFERON ALFA-2a, pre-filled syringes, 180 micrograms and RIBAVIRIN, tablets, 200 mg, (168 tablets) and PEGINTERFERON ALFA-2a, pre-filled syringes, 135 micrograms, Pegasys RBV®
Page last updated: 21 October 2010
Public Summary Document
Product: RIBAVIRIN, tablets, 200 mg, (112 tablets,
140 tablets and 168 tablets) and PEGINTERFERON ALFA-2a, pre-filled
syringes, 180 micrograms and RIBAVIRIN, tablets, 200 mg, (168
tablets) and PEGINTERFERON ALFA-2a, pre-filled syringes, 135
micrograms, Pegasys RBV®
Sponsor: Roche Products Pty Ltd
Date of PBAC Consideration: July 2010
1. Purpose of Application
To extend the Section 100 listing for the treatment of chronic
hepatitis C (CHC) to include patients who have failed one prior
attempt at interferon based therapies (non-pegylated or
pegylated).
Highly Specialised Drugs (HSD) are medicines for the treatment of
chronic conditions that, because of their clinical use or other
special features, are restricted to supply through public or
private hospitals that have appropriate specialist facilities. To
prescribe these medicines under the PBS, medical practitioners must
be affiliated with these specialist public hospital units. A
medical practitioner or non-specialist hospital medical
practitioner, who is not affiliated with the public hospital, may
only prescribe HSD to provide maintenance therapy under the
guidance of the treating specialist affiliated with the public
hospital.
2. Background
At its June 2003 meeting, the PBAC recommended a Section 100
listing for Pegasys RBV for treatment of chronic hepatitis C in
patients 18 years of age with compensated liver disease and who
have not received prior interferon based therapies who satisfy
certain criteria on a cost-minimisation basis compared with
ribavirin and peginterferon alfa-2b (Pegatron®).
Listing was effective from 1 November 2003.
At the July 2009 meeting, the PBAC rejected a minor submission to
extend the listing of Pegasys RBV to include treatment of patients
with chronic hepatitis C who have failed one prior attempt at
interferon based therapy.
The PBAC considered that both the clinical and economic data to
support the request required evaluation, and determined that the
request required a major submission.
3. Registration Status
Peginterferon alfa-2a was TGA registered on 31 March 2009 for the following indications:
- Peginterferon alfa-2a monotherapy is indicated for the treatment chronic hepatitis C in patients who have received no prior interferon therapy (treatment naïve patients).
- The combination of peginterferon alfa-2a and ribavirin is indicated for the treatment of chronic hepatitis C in treatment naïve patients and patients who have failed previous treatment with interferon alfa (pegylated or non-pegylated) alone or in combination with ribavirin.
4. Listing Requested and PBAC’s View
Section 100 (Highly Specialised Drugs Program)
Private hospital authority required
Patients who have failed one prior attempt at interferon based
therapies (non-pegylated or pegylated).
Treatment, managed by an accredited treatment centre, of chronic
hepatitis C in patients 18 years or older who have compensated
liver disease and who have received no more than one prior
treatment with interferon alfa or peginterferon alfa for hepatitis
C and who satisfy all of the following criteria:
(1) Documented chronic hepatitis C infection (repeatedly anti-HCV
positive and HCV RNA positive);
(2) Female patients of child-bearing age are not pregnant, not
breast-feeding, and both patient and their partner are using
effective forms of contraception (one for each partner). Male
patients and their partners are using effective forms of
contraception (one for each partner). Female partners of male
patients are not pregnant.
The treatment course is limited to 48 weeks. Patients may only
continue treatment after the first 12 weeks of treatment if plasma
HCV RNA is not detectable by an HCV RNA qualitative assay at week
12.
For PBAC’s view, see Recommendation and
Reasons.
5. Clinical Place for the Proposed Therapy
The proposed extension to the listing for Pegasys RBV would provide
an additional treatment option for patients with chronic hepatitis
C who have failed one previous course of therapy with interferon
alfa (non-pegylated or pegylated) with or without ribavirin.
6. Comparator
The submission appropriately nominated peginterferon-alfa-2b plus
RBV as the comparator.
7. Clinical Trials
The submission defined four subgroups of eligible patients. The basis of the comparison
in each subgroup is outlined below.
1. Non-responders
i. Previous pegylated interferon plus ribavirin therapy: a comparison of two single arms from different randomised trials (REPEAT, METRO) and one case series for Pegasys RBV (HALT-C); and a case series for Pegatron CT (EPIC-3).
ii. Previous standard interferon plus ribavirin therapy: one direct randomised trial comparing Pegasys RBV with Pegatron CT (Scotto 2008).
A non-responder was defined as a patient who did not achieve viral suppression (serum
hepatitis C virus ribonucleic acid, HCV RNA, remained detectable) despite a minimum
of 12 weeks of treatment.
2.Relapsers
i. Previous pegylated interferon plus ribavirin therapy: an indirect comparison of one case series for Pegasys RBV (WV16143) with a case series for Pegatron CT (EPIC-3).
ii. Previous standard interferon plus ribavirin therapy: no studies of the effectiveness of Pegasys RBV in this patient subgroup were located; a comparison with Pegatron CT could not be performed.
Scotto (2008) has limited relevance as this study involved prior failure with standard
interferon plus ribavirin and not many Australian patients receive standard therapy.
Further, the non-comparative studies are more relevant in the Australian context as
most non-responders and relapsers will have failed peginterferon plus ribavirin.
The key trials and non-comparative studies published at the time of submission are
shown in the table below:
| Trial ID/First author | Protocol title/ Publication title | Publication citation |
| Direct randomised trial – Pegasys RBV vs Pegatron CT | ||
| Scotto 2008 (NR after IFN + RBV) Scotto G et al 2008 | Peg-interferon alpha-2a versus peg-interferon alpha-2b in non-responders with HCV active chronic hepatitis: a pilot study. | J Interferon Cytokine Res 2008; 28(10):623-629. |
| Scotto G et al 2008 | Early and sustained virological response in non-responders with chronic hepatitis C: a randomized open-label study of pegylated interferon-alpha-2a versus pegylated interferon-alpha-2b. | Drugs 2008; 68(6):791-801. |
| Pegasys RBV | ||
| Single arms of randomised trials | ||
| REPEAT (NR after PEG-IFN + RBV) | ||
| Jensen DM et al 2009 | Re-treatment of patients with chronic hepatitis C who do not respond to peginterferon-α2b. | Ann Intern Med 2009; 150(8):528-540. |
| Jensen DM and Marcellin P 2005 | Rationale and design of the REPEAT study: a phase III, randomized, clinical trial of peginterferon alfa-2a (40kDa) plus ribavirin in non-responders to peginterferon alfa-2b (12kDa) plus ribavirin. | Eur J Gastroenterol Hepatol 2005; 17(9):899-904. |
| METRO (NR after PEG-IFN + RBV) Rustgi VK et al 2009 | Merimepodib, pegylated interferon, and ribavirin in genotype 1 chronic hepatitis C pegylated interferon and ribavirin non-responders. | Hepatology 2009; 50(6):1719-1726. |
| Non-comparative studies | ||
| HALT-C (NR after PEG-IFN or IFN ± RBV) Bonkovsky HL et al 2007 | Health-related quality of life in patients with chronic hepatitis C and advanced fibrosis. | Journal of Hepatology 2007; 46(3):420-431. |
| Everson GT et al 2006 | Impact of disease severity on outcome of antiviral therapy for chronic hepatitis C: lessons from the HALT-C trial. | Hepatology 2006; 44(6):1675-1684. |
| Lee MW et al 2004 | Evolution of the HALT-C trial: pegylated interferon as maintenance therapy for chronic hepatitis C in previous interferon nonresponders. | Control Clin Trials 2004; 25(5):472-492. |
| Shiffman ML et al 2007 | Impact of reducing peginterferon alfa-2a and ribavirin dose during retreatment in patients with chronic hepatitis C. | Gastroenterology 2007; 132(1):103-112. |
| Shiffman ML et al 2004 | Peginterferon alfa-2a and ribavirin in patients with chronic hepatitis C who have failed prior treatment. | Gastroenterology 2004;126(4):1015-1023. |
| WV16143 (Relapsers after PEG-IFN + RBV) | J Viral Hepatitis 2006; 13(7):435-440. | |
| Berg C et al 2006 | Re-treatment of chronic hepatitis C patients after relapse: efficacy of peginterferon-alpha-2a (40kDa) and ribavirin. | |
| Pegatron CT | ||
| Single arms of randomised trials | ||
| Mathewl 2006 (NR and relapsers after IFN ± RBV) Mathew A et al 2006 | Sustained viral response to pegylated interferon α-2b and ribavirin in chronic hepatitis C refractory to prior treatment. | Dig Dis Sci 2006; 51(11):1956-1961. |
| Mathew A et al 2006 | Improvement in quality of life measures in patients with refractory hepatitis C, responding to re-treatment with pegylated interferon alpha-2b and ribavirin. | Health Qual Life Outcomes 2006; 4, article number 30. |
| Bergmann JF et al 2007 (NR and relapsers after IFN ± RBV) | Gamma-glutamyltransferase and rapid virological response as predictors of successful treatment with experimental or standard peginterferon-α-2b in chronic hepatitis C non-responders. | Liver Int 2007; 27(9):1217-1225. |
| Non-comparative studies | ||
| EPIC-3 Poynard T et al 2009 (NR or relapsers after IFN +RBV or PEG-IFN + RBV) | Peginterferon alpha-2b and ribavirin: effective in patients with hepatitis C who failed interferon alfa/ribavirin therapy. | Gastroenterology 2009;136(5):1618-1628. |
| Carnicer F et al 2005 (NR and relapsers after IFN ± RBV) | Treatment with pegylated interferon alpha 2b and ribavirin in patients unresponsive to previous treatments with standard interferon as monotherapy or combined with ribavirin. | Rev Esp Enferm Dig 2005; 97(5):306-316. |
| Goncales Jr FL et al 2006 (Treatment naive and NR or relapsers after IFN + RBV) | Weight-based combination therapy with peginterferon α-2b and ribavirin for naive, relapser and non-responder patients with chronic hepatitis C. | Braz J Infect Dis 2006; 10(5):311-316. |
| Moucari R et al 2007 (NR and relapsers after IFN + RBV) | High predictive value of early viral kinetics in re-treatment with peginterferon and ribavirin of chronic hepatitis C patients non-responders to standard combination therapy. | J Hepatol 2007; 46(4): 596-604. |
| Myers RP et al 2004 (HIV/HCV co-infected NR and relapsers after IFN ± RBV) | Pegylated interferon alpha 2b and ribavirin in HIV/hepatitis C virus-co-infected non-responders and relapsers to IFN-based therapy. | AIDS 2004; 18(1):75-79. |
| Supportive trials and studies | ||
| Meta-analysis Pegasys RBV vs Pegatron CT | ||
| Awad T et al 2010 (Meta-analysis mainly treatment-naïve) | Peginterferon alpha-2a is associated with higher sustained virological response than pegatron alfa-2b in chronic hepatitis C: systematic review of randomized trials. | Hepatology 2010; 51(4):1176-1184. |
HCV=hepatitis C virus; HIV=human immunodeficiency virus; IFN=standard interferon;
NR=non-responder; PEG-IFN=pegylated interferon; RBV=ribavirin
8. Results of Trials
As peginterferon alfa (either 2a or 2b) plus ribavirin is the
standard of care for treatment naïve CHC patients in
Australia, patients who have failed on or relapsed after prior
peginterferon alfa plus ribavirin are likely to represent the most
common subgroup of patients eligible for PBS funded
re-treatment.
Sustained virological response (SVR) was the primary outcome in the
direct randomised trial and the majority of the studies presented
in the submission. It was consistently defined as undetectable
serum HCV RNA at week 72 (24 weeks after the end of treatment). On
the basis of the results for SVR in the direct randomised trial
(Scotto 2008), including patients who failed to respond to prior
therapy with standard interferon plus ribavirin, the submission
concluded that Pegasys RBV for 48 weeks is no worse than Pegatron
CT for 48 weeks in terms of effectiveness in the treatment of
previously treated CHC in this patient subgroup. As neither Scotto
2008 nor the submission specified a non-inferiority margin, this
claim was based on a finding of no statistical difference in
treatment effect between the two treatment arms.
The submission noted from the results for SVR from Scotto 2008 and
the non-comparative studies, for each of the four patient subgroups
(grouped by genotype, since this is a well-established treatment
modifier) that the majority of point estimates for SVR rates were
higher for Pegasys RBV than for Pegatron CT; in particular, the
point estimates were higher for patients with prior peginterferon
alfa treatment failure and HCV genotype 1, who represent the most
commonly retreated patients in current Australian practice.
The main adverse events (AEs) observed in the direct randomised
trial (Scotto 2008) are summarised as follows:
The incidence and severity of adverse events were similar in both
peginterferon groups. Four in the Pegasys RBV arm (N=71) and three
in the Pegatron CT arm (N=72), experienced severe psychiatric
disorders resulting in therapy discontinuation. A further treatment
discontinuation was necessary in five patients in the Pegasys RBV
arm and three in the Pegatron CT arm due to marked weight loss. One
patient in each arm discontinued therapy because of severe
headaches and one in the Pegatron CT arm for continuous
fever.
Among the remaining patients, an influenza-like syndrome was
reported in 42 patients in the Pegasys RBV arm and 44 patients in
the Pegatron CT arm. Anaemia (Hb < 10 g/dL) was observed in nine
Pegasys RBV and in ten Pegatron CT patients. Thrombocytopenia
(<75,000/mm3) was reported in 13 patients in the
Pegasys RBV arm and 10 in the Pegatron CT arm. Leucopenia
(<3,000/mm3) was observed in ten Pegasys RBV and
seven Pegatron CT patients.
Six patients in the Pegasys RBV group and three in the Pegatron CT
group with leucopenia and/or thrombocytopenia required a dose
reduction of pegylated interferon, while five subjects in the
Pegasys RBV group and three in the Pegatron CT group required a
reduction in the dose of ribavirin. No pathological alterations in
creatinine and uric acid serum levels were reported, but in all
subjects a moderate hyperbilirubinaemia associated with
ribavirin-induced haemolysis was observed.
Scotto (2008) was insufficiently powered to reliably assess the
relative safety of Pegasys RBV versus Pegatron CT. There were no
comparative safety data in special patient subgroups, such as
patients with HIV/HCV co-infection, and patients with renal
impairment.
9. Clinical Claim
The submission described Pegasys RBV for 48 weeks as non-inferior,
in terms of both comparative effectiveness and comparative safety,
to Pegatron CT for 48 weeks for re-treatment of CHC patients who
have failed one prior attempt at interferon based therapies.
For PBAC’s view, see Recommendation and
Reasons.
10. Economic Analysis
The submission presented a cost minimisation analysis. The
base-case analysis presented the average cost per patient of a
course of treatment with Pegasys RBV and Pegatron CT, accounting
for the proportion of patients who discontinue treatment at week
12, and assuming those continuing treatment receive a total of 48
weeks of therapy.
The equi-effective doses were considered to be those recommended in
the respective Product Information (PI) documents for prior
treatment failure. The economic evaluation used the doses
recommended in the relevant PI’s, and a treatment duration of
48 weeks for all patients. However, the recommended duration of
treatment for patients with genotype 1 or 4 infection in the
Pegasys RBV PI is up to 72 weeks.
Drug acquisition costs were the only costs included in the
cost-minimisation analysis.
The submission’s cost minimisation analysis indicated that
Pegasys RBV was cost saving compared with Pegatron CT for the
treatment of CHC patients who had failed prior interferon based
therapy. The evaluation considered that there was considerable
uncertainty in the proportion of patients who would meet the
continuation criterion and receive the full 48 week course of
therapy; the magnitude of any saving was largely dependent on this
proportion.
For PBAC’s view, see Recommendation and
Reasons.
11. Estimated PBS Usage and Financial Implications
The likely number of patients/year was estimated by the submission to be less than
10,000 in Year 5. The financial savings per year to the PBS were estimated by the submission to be less than $10 million
in Year 5. The submission’s estimates were considered uncertain.
12. Recommendation and Reasons
The PBAC recommended the Section 100 Highly Specialised Drug listing of peginterferon
alfa-2a with ribavirin (Pegasys RBV) be extended to include the treatment of patients
with hepatitis C who have failed one prior attempt at interferon based therapies (non-pegylated
or pegylated). Listing was recommended on a cost-minimisation basis with peginterferon
alfa-2b with ribavirin (Pegatron), for 48 weeks of treatment.
The PBAC noted that the evidence for the comparative effectiveness of Pegasys RBV
versus Pegatron CT for a treatment course of 48 weeks in genotype 1, 2, 3 and 4 infection,
in both non-responders and relapsers to pegylated interferon plus ribavirin, who are
likely to represent the majority of re-treated patients in Australia, is derived from
non-comparative studies, with considerable potential for confounding and major biases.
Nonetheless, the Committee accepted that it was very unlikely that Pegasys RBV would
be less effective than Pegatron CT.
The PBAC further considered that the comparative evidence to support the claim that
Pegasys RBV is non-inferior to Pegatron in terms of safety in chronic hepatitis C
patients who have previously failed prior non-pegylated interferon based therapy is
equally limited. However, there are no biological grounds that would be expected to
result in differences and the PBAC agree that the submissions claim that Pegasys RBV
is non-inferior in terms of safety to Pegatron CT is reasonable.
The PBAC noted that at the prices proposed in the submission, Pegasys RBV will be
cost-saving compared to Pegatron CT. This is because the doses of ribavirin in the
Pegasys RBV regimen, and the doses of both peginterferon alfa-2b and ribavirin in
the Pegatron CT regimen, are dependent on patient bodyweight. The distribution of
bodyweight in the eligible population influences the outcome of the cost-minimisation
analysis, as the incremental cost of Pegatron CT versus Pegasys RBV increases with
increasing bodyweight, and it is apparent that the proportion of patients with higher
body weight utilising Pegatron CT is higher than was estimated at the time of listing.
The PBAC requested that the Minister and Pricing Authority be advised that it is appropriate
to review the prices of Pegatron across all indications to align them with the lower
prices of Pegasys.
Recommendation:
RIBAVIRIN, tablets, 200 mg, (112 tablets, 140 tablets and 168 tablets) and PEGINTERFERON
ALFA-2a, pre-filled syringes, 180 micrograms and RIBAVIRIN, tablets, 200 mg, (168
tablets) and PEGINTERFERON ALFA-2a, pre-filled syringes 135 micrograms
Extend the current restriction to include:
Restriction:Highly Specialised Drugs Program
Authority Required (STREAMLINED)
Private hospital authority required
Patients who have failed one prior attempt at interferon based therapies (non-pegylated or pegylated).Treatment, managed by an accredited treatment centre, of chronic hepatitis C in patients 18 years or older who have compensated liver disease and who have received no more than one prior treatment with interferon alfa or peginterferon alfa for hepatitis C and who satisfy all of the following criteria:
(1) Documented chronic hepatitis C infection (repeatedly anti-HCV positive and HCV RNA positive);
(2) Female patients of child-bearing age are not pregnant, not breast-feeding, and both patient and their partner are using effective forms of contraception (one for each partner). Male patients and their partners are using effective forms of contraception (one for each partner). Female partners of male patients are not pregnant.
The treatment course is limited to 48 weeks. Patients may only continue treatment after the first 12 weeks of treatment if plasma HCV RNA is not detectable by an HCV RNA qualitative assay at week 12.
Note: Treatment centres are required to have access to the following appropriate specialist facilities for the provision of clinical support services for hepatitis C:
(a) a nurse educator/counsellor for patients; and
(b) 24 hour access by patients to medical advice; and
(c) an established liver clinic; and
(d) facilities for safe liver biopsy.
Maximum quantity: 2
Repeats: 5
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 had no further comment.
