Ribavirin, capsules, 200 mg, (84 or 112 capsules) with peginterferon alfa-2b, single use injection pens, 50, 80, 100 or 120 micrograms, Pegatron® - July 2011
Ribavirin and peginterferon alfa-2b, pack containing 84 capsules ribavirin 200 mg and 4 single use injection pens containing peginterferon alfa-2b powder for injection 50 micrograms with diluent; pack containing 84 capsules ribavirin 200 mg and 4 single use injection pens containing peginterferon alfa-2b powder for injection 80 micrograms with diluent; pack containing 84 capsules ribavirin 200 mg and 4 single use injection pens containing peginterferon alfa-2b powder for injection 100 micrograms with diluent; pack containing 84 capsules ribavirin 200 mg and 4 single use injection pens containing peginterferon alfa-2b powder for injection 120 micrograms with diluent; pack containing 112 capsules ribavirin 200 mg and 4 single use injection pens containing peginterferon alfa-2b powder for injection 50 micrograms with diluent; pack containing 112 capsules ribavirin 200 mg and 4 single use injection pens containing peginterferon alfa-2b powder for injection 100 micrograms with diluent, Pegatron®
Page last updated: 28 October 2011
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Public Summary Document
Product: Ribavirin and peginterferon alfa-2b,
pack containing 84 capsules ribavirin 200 mg and 4 single use
injection pens containing peginterferon alfa-2b powder for
injection 50 micrograms with diluent; pack containing 84 capsules
ribavirin 200 mg and 4 single use injection pens containing
peginterferon alfa-2b powder for injection 80 micrograms with
diluent; pack containing 84 capsules ribavirin 200 mg and 4 single
use injection pens containing peginterferon alfa-2b powder for
injection 100 micrograms with diluent; pack containing 84 capsules
ribavirin 200 mg and 4 single use injection pens containing
peginterferon alfa-2b powder for injection 120 micrograms with
diluent; pack containing 112 capsules ribavirin 200 mg and 4 single
use injection pens containing peginterferon alfa-2b powder for
injection 50 micrograms with diluent; pack containing 112 capsules
ribavirin 200 mg and 4 single use injection pens containing
peginterferon alfa-2b powder for injection 100 micrograms with
diluent, Pegatron®
Sponsor: Merck Sharp and Dohme (Australia) Pty Ltd
(as Schering-Plough Pty Ltd)
Date of PBAC Consideration: July 2011
1. Purpose of Application
The submission requested an extension of the current Section 100
(Highly Specialised Drugs Program) listing to include treatment of
chronic hepatitis C (CHC) in children and adolescents with a
bodyweight of greater than or equal to 27 kg with compensated liver
disease and who have not received previous interferon
treatment.
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 March 2002 and September 2002 PBAC meetings, applications to
list Pegatron combination therapy were rejected on the basis of
uncertain but unfavourable cost-effectiveness.
At the March 2003 meeting the PBAC recommended listing for Pegatron
as a Section 100 (Highly Specialised Drugs Program) listing for
treatment of chronic hepatitis C in patients aged 18 years or older
who satisfy certain criteria on the basis of acceptable
cost-effectiveness. Listing was effective from 1 February
2004.
At the July 2008 meeting, the PBAC recommended the listing of
ribavirin and peginterferon alfa-2b on the PBS be extended to
include 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.
3. Registration Status
Ribavirin and peginterferon alfa-2b therapy is indicated for the
treatment of patients with chronic hepatitis C who are either
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.
Since 3 August 2011, ribavirin and peginterferon alfa-2b therapy is
also indicated for the treatment of chronic hepatitis C in children
and adolescents with a body weight of greater than or equal to 27
kg with compensated liver disease and who have not received
previous interferon treatment.
4. Listing Requested and PBAC’s View
The submission proposed extending the current listing to allow
patients aged less than 18 years to be treated with one course of
Pegatron irrespective of genotype and fibrosis score. Continuation
criteria for paediatric patients were proposed to be the same as
for treatment-naïve adult patients. No wording was proposed in
the submission.
For PBAC’s view, see Recommendation and
Reasons.
5. Clinical Place for the Proposed Therapy
The submission stated that there are currently no TGA registered or
PBS listed medicines for individuals (aged less than 18 years) with
chronic hepatitis C virus infection.
The submission proposed that extending Pegatron’s TGA
registration and PBS listing to cover patients aged less than 18
years would provide a treatment option for this patient
group.
6. Comparator
The submission nominated standard of care (i.e. no treatment
– the natural progression of hepatitis C disease virus
infection) as the main comparator. Paediatric patients are
currently eligible for treatment with interferon-based therapies on
the PBS once they reach 18 years of age.
The PBAC considered that a more appropriate comparator of standard
of care would have included the treatment of CHC in paediatric
patients with an interferon based therapy once the age of 18 is
reached, rather than no treatment over the lifetime of the patient,
as this would more accurately reflect current clinical
practice.
7. Clinical Trials
The submission presented one single arm case series (P02538) of 107 patients aged
between three and 17 years treated with 60 micrograms per metre squared per week peginterferon
alfa-2b and 15 mg per kg per day ribavirin.
Details of the published trial are presented in the table below.
| Analysis | Number of responders c | Percentage of responders | 95% confidence interval of the percentage |
| All genotypes | 51/74 | 68.9 | 57.1, 79.2 |
| Genotype 1 | 29/49 | 59.2 | 44.2, 73.0 |
| Genotype 2 | 11/12 | 91.7 | 61.5, 99.8 |
| Genotype 3 (all) | 8/9 | 88.9 | 51.8, 99.7 |
| 24 weeks | 7/7 | 100 | 59.0, 100 a |
| 48 weeksb | 1/2 | 50 | 1.3, 98.7 |
| Genotype 4 | 3/4 | 75 | 19.4, 99.4 |
a one-sided 97.5% confidence interval, a proportion of these subjects were incorrectly
allocated to 24 weeks treatment and should have received 48 weeks by protocol
b excluded from the economic analysis
c responders are those who achieved SVR at 24 weeks post-treatment
The wide confidence intervals reflected the small sample sizes for some of the genotype
subgroups.
For PBAC’s comments on these results, see Recommendations and Reasons.
Slower growth velocities compared with age and gender standardised averages for the
US population were reported in paediatric patients treated with combination peginterferon
alfa-2b and ribavirin in study P02538. The sponsor is continuing to follow study subjects
of P02538 for five years to investigate this.
The periodic safety updates for both peginterferon alfa-2b and ribavirin from 25th of July 2009 to 24th July 2010 were provided along with the main submission. No safety concerns were reported
that warranted alterations to the reference safety information for either drug.
No deaths were reported during the study period. The most common adverse events recorded
while on treatment were fever (80%), headache (66%), vomiting (34%), neutropenia (33%),
fatigue (30%), anorexia (29%), inflammation at injection site (29%), and abdominal
pain (26%).
While psychiatric adverse events were common and reported in 28% of subjects in the
key study, none met the criteria for a serious adverse event and no patient discontinued
treatment or required a dose modification because of psychiatric adverse events.
9. Clinical Claim
The submission asserted that combination peginterferon alfa-2b and
ribavirin for the treatment of chronic hepatitis C in a paediatric
population is superior to standard of care (no treatment) in terms
of effectiveness and inferior in terms of comparative safety. The
PBAC accepted this claim.
10. Economic Analysis
A stepped economic evaluation was presented. The economic
evaluation was a cost-utility analysis and took a health care
sector perspective. The Markov model had an 88 year duration
(lifetime) with an annual cycle length.
The model compared combination peginterferon alfa-2b and ribavirin
with standard care (no treatment) for the treatment of paediatric
patients with CHC. The submission stated that there was little
value in modelling downstream adult treatment.
Patients entered the model as viral positive with mild CHC, and
could become viral negative by achieving SVR following treatment
(75.9% in cycle 0) or through spontaneous viral clearance (2.4% per
annum until 18 years and 0.2% per annum thereafter). While patients
could progress to more severe health states from a negative viral
state (0.0009% per annum), ostensibly, only viral positive patients
could progress through the model.
Step one of the evaluation included only the cost of treatment
(with combination peginterferon alfa-2b and ribavirin and the
required eligibility and monitoring tests) and the rate of SVR
achieved across both arms.
Step two reported on the incremental QALYs over a two year period
(without considering the disutility associated with treatment)
while still only considering the costs described in step 1.
Step three represented the full model of 88 years in duration with
all health care costs and utility weights calculated for downstream
health states.
The incremental cost per QALY of paediatric treatment compared to
delaying treatment until 18 years (the current situation) was
unknown. The submission calculated an ICER of less than $15,000 but
did not incorporate the cost or QALY gains for adult interferon
treatment of CHC in the comparator arm.
The PBAC considered there was uncertainty in the economic model in
the assumption of no treatment as the comparator as this ascribed
the cost savings and benefits of current adult treatment to the
listing requested. However, overall the PBAC considered that
ribavirin with peginterferon alfa-2b for the treatment of chronic
hepatitis C in patients under the age of 18 years who have not
received previous interferon treatment was of acceptable cost
effectiveness.
11. Estimated PBS Usage and Financial Implications
The submission estimated the likely number of patients treated to
be less than 10,000 patients in year 5.
The financial cost to the PBS was estimated in the submission to be
less than $10 million in year 5. The net cost to the PBS, excluding
co-payments and the cost off-set by the displacement of future PBS
drug use, was not estimated by the submission.
12. Recommendation and Reasons
The PBAC recommended extending the listing of ribavirin with peginterferon alfa-2b
for the treatment of chronic hepatitis C to patients under the age of 18 years who
have not received previous interferon treatment on the basis of acceptable cost effectiveness
compared with standard of care, in the context of a high clinical need.
The PBAC noted that the Paediatric Medicines Advisory Group (PMAG) had identified
peginterferon alfa-2b in combination with ribavirin in the treatment of chronic hepatitis
C (CHC) virus infection in children as a treatment with a high clinical need in the
paediatric health setting.
The PBAC considered that a more appropriate comparator of standard of care would have
included the treatment of CHC in paediatric patients with an interferon based therapy
once the age of 18 is reached, rather than no treatment over the lifetime of the patient,
as this would more accurately reflect current clinical practice.
The submission presented one single arm case series (P02538) of 107 patients aged
between three and 17 years treated with 60 micrograms per metre squared per week peginterferon
alfa-2b and 15 mg per kg per day ribavirin. The PBAC noted that study P02538 used
an oral liquid form of ribavirin which allowed for more precise dose titration than
is possible using the 200 mg capsules, however that this liquid form of ribavirin
is not currently marketed in Australia. The PBAC noted that study P02538 included
patients from the age of three, however that the sponsor requested that the listing
be limited to patients greater than or equal to 27 kg based on the lowest dose able
to be administered from the capsule form of ribavirin available in Australia. The
PBAC noted that it is likely that younger patients would not be able to be treated
with the capsule form of ribavirin and requested that the PMAG provide advice on the
clinical need for the treatment of younger patients (those less than 27 kg) and the
corresponding clinical need for the oral liquid form to be made available.
The PBAC noted that the primary outcome in study P02538 was the proportion of patients
achieving SVR. The PBAC noted that this is a surrogate outcome, however that SVR was
previously accepted in the context of adult CHC.
The PBAC was concerned with the slower growth velocities compared with age and gender
standardised averages for the US population reported in paediatric patients treated
with combination peginterferon alfa-2b and ribavirin in study P02538 and whether there
is any lasting detrimental effect upon the growth or maturation of patients with CHC.
The PBAC however noted that the sponsor is continuing to follow study subjects of
P02538 for five years to investigate this.
The PBAC considered there was uncertainty in the economic model in the assumption
of no treatment as the comparator as this ascribed the cost savings and benefits of
current adult treatment to the listing requested. However, overall the PBAC considered
that ribavirin with peginterferon alfa-2b for the treatment of chronic hepatitis C
in patients under the age of 18 years who have not received previous interferon treatment
was of acceptable cost effectiveness.
Recommendation: RIBAVIRIN and PEGINTERFERON ALFA-2b, pack containing 84 capsules ribavirin 200 mg
and 4 single use injection pens containing peginterferon alfa-2b powder for injection
50 micrograms with diluent; pack containing 84 capsules ribavirin 200 mg and 4 single
use injection pens containing peginterferon alfa-2b powder for injection 80 micrograms
with diluent; pack containing 84 capsules ribavirin 200 mg and 4 single use injection
pens containing peginterferon alfa-2b powder for injection 100 micrograms with diluent;
pack containing 84 capsules ribavirin 200 mg and 4 single use injection pens containing
peginterferon alfa-2b powder for injection 120 micrograms with diluent; pack containing
112 capsules ribavirin 200 mg and 4 single use injection pens containing peginterferon
alfa-2b powder for injection 50 micrograms with diluent; pack containing 112 capsules
ribavirin 200 mg and 4 single use injection pens containing peginterferon alfa-2b
powder for injection 100 micrograms with diluent
Restriction:
Authority Required (Streamlined) – Public Hospital
Authority Required (Private Hospital)
Patients naive to interferon based therapies (non-pegylated or pegylated)
Treatment, managed by an accredited treatment centre, of chronic hepatitis C in patients
weighing at least 27 kg
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.
The listing for patients who have failed one prior attempt is unchanged.
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
MSD was pleased to support this request from PMAG for the submission to extend the listing of PEGATRON to paediatric and adolescent patients with chronic hepatitis C. This listing will greatly improve the lives of those young people affected by this disease who would otherwise have no PBS subsidise.
