Ribavirin capsules 200 mg, (various quantities) and peginterferon alfa-2b, single use injection pens containing powder for injection in 50, 80, 100, 120 and 150 micrograms, Pegatron®, July 2008
Public summary document for Ribavirin capsules 200 mg, (various quantities) and peginterferon alfa-2b, single use injection pens containing powder for injection in 50, 80, 100, 120 and 150 micrograms, Pegatron®, July 2008
Page last updated: 31 October 2008
Public Summary Documents
Product: Ribavirin capsules 200 mg, (various
quantities) and peginterferon alfa-2b, single use injection pens
containing powder for injection in 50, 80, 100, 120 and 150
micrograms, Pegatron®
Sponsor: Schering-Plough Pty Ltd
Date of PBAC Consideration: July 2008
1. Purpose of Application
The submission sought an extension to the PBS eligibility criteria
(currently patients who are interferon alfa or peginterferon alfa
naïve) to include those who have failed one previous treatment
with interferon alfa (pegylated or non-pegylated) either as
combination therapy with ribavirin or as monotherapy.
2. Background
At the March 2002 PBAC meeting, an application to list Pegatron
combination therapy was rejected on the basis of uncertain but
unfavourable cost-effectiveness.
The economic model was presented in further detail and the number
of patients was revised upwards, substantially for the September
2002 submission. However, the application to list Pegatron was
rejected on the same grounds as the March 2002 meeting –
uncertain but unfavourable cost-effectiveness.
At the March 2003 meeting the PBAC recommended that a weighted
price be negotiated for Pegatron on a cost-effectiveness basis for
patients with genotypes 1, 4, 5 or 6 (about 60% patients in
Australia) and on a cost-minimisation basis for patients with
genotypes 2 or 3 (about 40% patients in Australia).
3. Registration Status
On 3 March 2008, the TGA extended the registration for Pegatron
combination therapy to include the treatment of chronic hepatitis C
in patients who are who have failed previous therapy with
interferon alfa (pegylated or nonpegylated) and ribavirin
combination therapy or interferon monotherapy.
Pegatron is currently registered for the following:
The treatment of chronic hepatitis C in patients who are treatment
naive or who had failed previous therapy with interferon alfa
(pegylated or nonpegylated) and ribavirin combination therapy or
interferon monotherapy.
Combination therapy is also indicated for the treatment of adult
patients with chronic hepatitis C with stable HIV co-infection, who
have not previously received interferon treatment. Patients must be
18 years of age or older and have compensated liver disease.
4. Listing Requested and PBAC’s View
Changes to the existing restriction wording are in
italics.
Section 100
Private hospital authority required
Notes:
Caution:
Treatment with peginterferon alfa has been associated with
depression and suicide in some patients. Patients with a history of
suicidal ideation or depressive illness should be warned of the
risks. Psychiatric status during therapy should be monitored.
Caution:
Ribavirin is a category X drug and must not be given to pregnant
women. Pregnancy in female patients or in the partners of male
patients must be avoided during treatment and during the 6 months
period after cessation of treatment.
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
attempt at interferon alfa or peginterferon alfa treatment
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.
Interferon alfa naïve
patients:
For patients with genotype 2 or 3 hepatitis C without hepatic
cirrhosis or bridging fibrosis, the treatment course is limited to
24 weeks. For hepatitis C patients with genotype 1, 4, 5 or 6 and
those genotype 2 or 3 patients with hepatic cirrhosis or bridging
fibrosis, the treatment course is limited to 48 weeks.
Patients with genotype 1, 4, 5 or 6 who are eligible for 48 weeks
of treatment may only continue treatment after the first 12 weeks
if the result of an HCV RNA quantitative assay (performed at the
same laboratory using the same test) shows that the plasma HCV RNA
has become undetectable or the viral load has decreased by at least
a 2 log drop. (An HCV RNA assay at week 12 is unnecessary for
genotype 2 and 3 patients because of the high likelihood of early
viral response by week 12).
Patients with genotype 1, 4, 5 or 6 who are viral positive at week
12 but have attained at least a 2 log drop in viral load may only
continue treatment after the first 24 weeks of treatment if plasma
HCV RNA is not detectable by an HCV RNA qualitative assay at week
24. Similarly, genotype 2 or 3 patients with hepatic cirrhosis or
bridging fibrosis may only continue treatment after the first 24
weeks if plasma HCV RNA is not detectable by an HCV RNA qualitative
assay at week 24. An HCV RNA qualitative assay at week 24 is
unnecessary for those patients with genotype 1, 4, 5 or 6 who
became viral negative at week 12.
Patients who have failed one prior attempt at
interferon alfa based therapy:
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.
No change is requested to the currently approved packs or the
prices per pack.
See Recommendation and Reasons for PBAC’s
view.
5. Clinical Place for the Proposed Therapy
The proposed change in listing will have no effect on pegylated
interferon alfa treatment naïve patients but will make
Pegatron available for patients who have failed one previous course
of therapy with interferon alfa (pegylated or non-pegylated) with
or without ribavirin. Patients who failed an initial attempt at
treatment are currently ineligible for any further therapy on the
PBS.
6. Comparator
The submission nominated usual standard of care as the main
comparator because patients who have failed an initial attempt at
interferon alfa monotherapy or interferon alfa combination therapy
(pegylated or non-pegylated) are ineligible for any further courses
of therapy on the PBS.
The PBAC considered this was appropriate.
7. Clinical Trials
The submission presented nine prospective non-comparative studies:
- five case series of peginterferon alfa-2b plus ribavirin combination; and
- single arms extracted from four randomised controlled trials comparing different dosage regimens of peginterferon alfa-2b plus ribavirin combination.
The non-comparative studies and associated reports published at the
time of submission are as follows:
| Study ID | Protocol title/ Publication title | Publication citation |
| P02370 | Predictors of Sustained Viral Response in the Retreatment of Previous Interferon/Ribavirin Non-responders: Results from the EPIC3 Program. | Poynard T et al. Global Antiviral Journal 2007 (HEP DART 2007 - Frontiers in Drug Development for Viral Hepatitis, Lahaina, Hawaii); Volume 3 (Supplement): abstract Number 110. |
| Fibrosis stage is not a pre-determinant of significant adverse events in previous interferon (IFN)-ribavirin (riba) treatment failures receiving Peg-interferon alfa 2b/riba weight-based dosing: results from the EPIC3 Program. | Terg R et al Hepatology 2005 (56th Annual Meeting American Association Study Liver, AASLD, San Francisco, CA, USA); 42(4): Supplement 1, abstract 853, 530-1A | |
| Interferon (IFN) induced thrombocytopenia is independent of level of fibrosis in patients with chronic hepatitis C (CHC): results from the EPIC 3 Program. | Schiff E et al. Hepatology 2005 (56th Annual Meeting American Association Study Liver Disorders, AASLD, San Francisco, CA, USA); 42(4): Supplement 1, abstract 854, 531-2A | |
| Sustained virologic response (SVR) with PEG-Interferon-alfa 2b/ribavirin weight-based dosing in previous interferon/ribavirin HCV treatment failures; Week 12 virology as a predictor of SVR in the EPIC3 Trials. | Poynard T et al Gastroenterology 2005 (Dig. Dis. Wk., (DDW), Chicago, IL, USA); 128(4), Supplement 2, abstract 5 | |
| Week twelve virology predicts SVR in previous interferon/ribavirin treatment failures receiving PEG-Intron/REBETOL (PR) weight-based dosing (WBD). | Poynard T et al Journal of Hepatology 2005; (40th Annual Meeting of the European Association Study Liver, EASL, Paris, France), 42(2), Supplement, abstract 96 | |
| High early viral response (EVR) with PEGINTRON/ REBETOL (PR) weight-based dosing (WBD) in previous interferon/ribavirin HCV treatment failures; early results of the EPIC3 trial. | Poynard T et al. Hepatology 2004, (55th Annual Meeting American Association Study Liver Disorders (AASLD), Boston, MA, 40(4), supplement 1, abstract 170 | |
| Bergmann 2007 | (gamma)-glutamyltransferase and rapid virological response as predictors of successful treatment with experimental or standard peginterferon-(alpha)-2b in chronic hepatitis C non-responders. | Bergmann JF et al. Liver International 2007; 27:1217-25 |
| Goncales 2006 | Weight-based combination therapy for peginterferon alfa-2b and ribavirin for naive, relapser and non-responder patients with chronic hepatitis C. | Goncales FL, et al. The Brazilian Journal of Infectious Diseases 2006; 10(5):311-16 |
| Hasan 2004 | Peginterferon alpha-2b plus ribavirin with or without amantidine for the treatment of non-responders to standard interferon and ribavirin. | Hasan F ,et al. Antiviral Therapy 2004; 9:499-503 |
| Mathew 2006 | Improvement in quality of life measures in patients with refractory hepatitis C, responding to re-treatment with Pegylated interferon alpha -2b and ribavirin. | Mathew A, et al. Health and quality of life outcomes 2006 [electronic resource] 4:30. |
| Sustained virologic response to pegylated interferon (alpha)-2b and ribavirin in chronic hepatitis C refractory to prior treatment. | Mathew A, et al. Digestive Diseases and Sciences 2006; 51:1956-61 | |
| Maynard 2006 | Amantadine triple therapy for non-responder hepatitis C patients. Clues for controversies (ANRS HC 03 BITRI). | Maynard M, et al. Journal of Hepatology 2006; 44:484-90 |
| Moucari 2007 | High predictive value of early viral kinetics in retreatment with peginterferon and ribavirin of chronic hepatitis C patients non-responders to standard combination therapy. | Moucari R, et al. Journal of Hepatology 2007; 46:596-604 |
| Myers 2004 | Pegylated interferon alpha 2b and ribavirin in HIV/hepatitis C virus-co-infected non-responders and relapsers to IFN-based therapy. | Myers RP, et al. AIDS 2004; 18:75–9 |
| Taliani 2006 | Pegylated interferon alfa-2b plus ribavirin in the retreatment of interferon-ribavirin nonresponder patients. | Taliani G, et al. Gastroenterology 2006; 130:1098-106 |
8. Results of Trials
The key results are summarised in the table below.
Sustained virological response (SVR) reported in the studiesa
| Study | N | SVR n (%) | CI b |
| P02370 | 1,336 | 303 (22.7) | 99% CI (19.7-25.6) |
| Australian subgroup | 76 | 26 (34.2) | NR |
| Non-Australian subgroup | 1,265 | 256 (20.2) | NR |
| Goncales 2006 | 66 | 31 (46.9) | NR |
| Moucari 2007 | 154 | 44 (28.6) | NR |
| Taliani 2006 | 141 | 28 (19.6) | NR |
| Bergmann 2007 | 30 | 11 (36.7) | NR |
| Hasan 2004 | 21 | 1 (4.8) | NR |
| Mathew 2006 | 72 | 15 (20.8) | NR |
| Maynard 2006 | 99 | 16 (16.2) | NR |
| Myers 2004 | 32 | 5 (15.6) | NR |
a defined as undetectable plasma HCV-RNA after 24 weeks follow up post treatment; b
standard deviations or standard error are not reported in the published reports; CI
= confidence interval;
NR = not reported; SVR = sustained virological response
Twenty-two percent of subjects in study P02370 achieved a SVR, which the submission
attributed to peginterferon alfa-2b and ribavirin combination therapy. SVR varied
between 4.8% and 46.9% across the studies.
In study P02370, 97.2% (1,304) of subjects experienced a treatment emergent adverse
event (AE) and 8.8% (118) of subjects reported a serious adverse event (SAE). 6.6%
(89) of subjects discontinued treatment due to adverse events. The following reported
adverse events had the greatest incidence: headache (43%); pyrexia (41%); myalgia
(34%); fatigue (32%); nausea (25%); asthenia (24%); insomnia (23%); neutropenia (22%);
chills (21%); and influenza-like illness (20%). The most frequently reported SAEs
were: pneumonia (0.6%); neutropenia (0.4%), chest pain (0.4%), and suicidal ideation
(0.4%). Despite the lack of a safety comparison with standard care, it was clear that
most patients will experience adverse events when receiving peginterferon alfa-2b
and ribavirin combination therapy.
For PBAC’s comments on these trials, see Recommendations and Reasons.
9. Clinical Claim
The submission claimed peginterferon alfa-2b and ribavirin
combination therapy as superior in terms of comparative
effectiveness and inferior in terms of comparative safety over
standard care.
For PBAC’s view, see Recommendations and
Reasons.
10. Economic Analysis
The submission presented a stepped economic evaluation. The economic evaluation took a health care sector perspective and utilised a Markov model, constructed using TreeAge Pro 2007 Suite®. A cohort expected value analysis was employed. The model had a 53-year duration (lifetime), with an annual cycle length.
The model compared standard care or peginterferon alfa-2b and
ribavirin combination therapy for the treatment of patients with
CHC and moderate to severe fibrosis who have failed a previous
course of interferon based therapy, simulating the course of the
disease using fifteen health states. Patients entered the model in
either the viral positive moderate or cirrhotic stage. Patients
with mild fibrosis were not included in the model. As in the
previous submissions, the model was structured so that only
patients who were treated can become viral negative. Patients
transition from viral positive to viral negative status in the
first cycle only.
Patients accrued costs and quality adjusted life years (QALYs) in
each cycle of the model until death. QALYs were calculated from the
utility weights for each health state. Progression through the
health states was dependant upon viral status and disease stage. A
disutility weighting was applied in the first cycle of the model to
account for the reduced quality of life while undergoing
peginterferon α-2b and ribavirin combination therapy. The
utility values and transition probabilities applied in the model
were subject to uncertainty. The costs of drug therapy were
incurred in the first cycle of the Markov model only. In subsequent
cycles, the costs incurred relate to the cost of management of CHC
only. The resources included were drug costs and non-drug costs
(outpatient visit, FBE, ALT, TSH, HCV genotype assay, pregnancy
test, and PCR tests).
The incremental cost/extra QALY gained was estimated to be less
than $15,000.
Inspection of the expanded report in the TreeAge model for each
treatment arm by cycle indicated that the main contributors to the
overall incremental cost between the treatment arms were: (i) the
costs of peginterferon alfa-2b and ribavirin combination therapy;
(ii) the costs associated with hepatocellular carcinoma; and (iii)
the costs associated with the management of post-liver transplant.
The incremental QALY was mainly driven by: (i) the disutility
associated with peginterferon alfa-2b and ribavirin combination
therapy during the first year of the model; (ii) the utility
associated with viral positive and viral negative status; and (iii)
the difference in mortality, which was largely due to the
difference in deaths due to liver disease between the treatment
arms.
11. Estimated PBS Usage and Financial Implications
The likely number of patients per year was estimated to be less
than 10,000 in Year 3. The submission suggested that the treatment
of CHC with peginterferon and ribavirin combination therapies had
reached a maximum due to capacity constraints in the health system
in Australia for the treatment of patients with CHC. Financial
estimates were based on the assumption that services for the
treatment of CHC would be expanded in line with the recommendations
in the Hepatitis C Virus Projections Working Group 2006 (HCVPWG)
report.
The financial cost per year to the PBS was estimated to be in the
range of $30-$60 million in Year 1 beyond the current level of use
for peginterferon and ribavirin combination therapies, including
but not limited to, the combination for which listing is
sought.
12. Recommendation and Reasons
The PBAC recommended the listing of ribavirin and peginterferon
alfa-2b on the PBS for the treatment of chronic hepatitis C in
patients who have failed one prior attempt at interferon based
therapies (non-pegylated or pegylated) on the basis of acceptable
cost-effectiveness compared with usual standard care. The PBAC
noted that the requested price was higher than the current price,
but considered that although the cost-effectiveness of re-treatment
was acceptable at the higher price, the weighted average price
proposed by the sponsor in its pre-PBAC response relies on
acceptance of the assumption that a pre-determined proportion of
hepatitis C patients will be eligible for initial treatment and for
re-treatment. These proportions cannot be monitored in the future
due to the operation of S100 listing and an as such, the pricing
strategy proposed by the submission presents some financial risk to
the government.
The PBAC agreed that standard care was the appropriate comparator
but that this assumes that the health system is not subject to
capacity constraints. However, the PBAC noted that capacity
constraints in the delivery of care may limit the uptake of
hepatitis C treatment and that such constraints would impact on the
calculation of costs to the Government arising from the extension
of treatment to include patients who have failed previous therapy.
Capacity restraints may also impact on clinicians between faced
with the choice of treating a patient with one treatment failure or
treating a treatment naïve patient.
The PBAC agreed that although there is some uncertainty in relation
to the design of the studies presented in the submission
(non-comparative, open-label, non consecutive selection of cases)
and differences in the baseline characteristics between the
Australian cases in study P02370 and the population for whom PBS
listing is sought, the evidence provided supports the claim that
peginterferon alfa-2b and ribavirin combination therapy is superior
in terms of comparative effectiveness and inferior in terms of
comparative safety over standard care. The PBAC considered that the
method applied to stratify the proportion of patients with a SVR
for Australian cases in study P02370 was appropriate provided that
fibrosis stage is unrelated to genotype and fibrosis stage is
equally distributed across the genotypes.
The PBAC noted that the costs of managing and treating adverse
events associated with peginterferon alfa-2b and ribavirin
combination therapy were not included in the Markov model and
therefore treatment costs may be underestimated. Both the quality
of evidence used to derive the SVR rates and the exclusion of costs
for treating adverse events limit the validity of the ICER. The
model assumptions were considered reasonable but most sensitive to
model duration (53 years). The overall cost-effectiveness was
nonetheless acceptable.
Recommendation
RIBAVIRIN capsules 200 mg, (all the currently listed various
quantities and the new recommended pack size of 196 capsules) and
PEGINTERFERON ALFA-2b, single use injection pens containing powder
for injection in 50, 80, 100, 120 and 150 micrograms.
Restriction : Section 100 Private hospital authority
required
Notes:
Caution:
Treatment with peginterferon alfa has been associated with
depression and suicide in some patients. Patients with a history of
suicidal ideation or depressive illness should be warned of the
risks.
Psychiatric status during therapy should be monitored.
Caution:
Ribavirin is a category X drug and must not be given to pregnant
women. Pregnancy in female patients or in the partners of male
patients must be avoided during treatment and during the 6
months
period after cessation of treatment.
Patients naïve to 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 prior interferon alfa
or
peginterferon alfa treatment 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.
For patients with genotype 2 or 3 hepatitis C without hepatic
cirrhosis or bridging fibrosis, the treatment course is limited to
24 weeks. For hepatitis C patients with genotype 1, 4, 5 or 6 and
those genotype
2 or 3 patients with hepatic cirrhosis or bridging fibrosis, the
treatment course is limited to 48 weeks.
Patients with genotype 1, 4, 5 or 6 who are eligible for 48 weeks
of treatment may only continue treatment after the first 12 weeks
if the result of an HCV RNA quantitative assay (performed at the
same
laboratory using the same test) shows that the plasma HCV RNA has
become undetectable or the viral load has decreased by at least a 2
log drop. (An HCV RNA assay at week 12 is unnecessary for
genotype 2 and 3 patients because of the high likelihood of early
viral response by week 12).
Patients with genotype 1, 4, 5 or 6 who are viral positive at week
12 but have attained at least a 2 log drop in viral load may only
continue treatment after the first 24 weeks of treatment if plasma
HCV RNA
is not detectable by an HCV RNA qualitative assay at week 24.
Similarly, genotype 2 or 3 patients with hepatic cirrhosis or
bridging fibrosis may only continue treatment after the first 24
weeks if plasma
HCV RNA is not detectable by an HCV RNA qualitative assay at week
24. An HCV RNA qualitative assay at week 24 is unnecessary for
those patients with genotype 1, 4, 5 or 6 who became viral negative
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.
Restriction: Section 100 Private hospital
authority
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.
Pack size: 1 (with the capsule + syringe pack combinations to be
the same as those listed for treatment naïve patients,
together with the newly recommended pack containing containing 196
x 200 mg
capsules and 4 x single use injection pens containing peginterferon
alfa-2b powder for injection 150 micrograms with diluent)
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 chose not to comment.
