Infliximab, powder for IV infusion, 100 mg, Remicade® - March 2010
Public Summary Document for Infliximab, powder for IV infusion, 100 mg, Remicade® - March 2010
Page last updated: 02 July 2010
PDF printable version for INFLIXIMAB, powder for IV infusion, 100 mg, Remicade® (PDF 131 KB)
Public Summary Document
Product: INFLIXIMAB, powder for IV infusion, 100
mg, Remicade®
Sponsor: Schering-Plough Pty Ltd
Date of PBAC Consideration: March 2010
1. Purpose of Application:
The re-submission sought a Section 100 (Highly Specialised Drugs
Program) Public and Private Hospital Authority Required listing for
complex fistulising Crohn disease with a draining enterocutaneous
or rectovaginal fistula.
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:
Infliximab is currently listed for the treatment of active
ankylosing spondylitis, severe active rheumatoid arthritis, severe
active psoriatic arthritis, severe chronic plaque psoriasis and
severe refractory Crohn disease.
Infliximab has been considered on a number of occasions by the PBAC
for fistulising Crohn disease. At the December 2000 meeting an
application for an Authority required listing for treatment of
draining enterocutaneous fistulae in patients with fistulising
Crohn disease was rejected. The PBAC rejected the application
because of the unknown clinical meaning of the trial endpoint,
which did not necessarily indicate healing of fistulae, and
unacceptable cost-effectiveness.
In September 2001, the PBAC rejected a resubmission because of
unacceptably high cost-effectiveness ratios.
In a minor submission to the December 2001 meeting, the PBAC was
asked to re-consider its decision to reject the listing of
infliximab for fistulising Crohn disease. In the absence of any
further information in support of the proposal that listing should
be recommended on the basis of ‘rule of rescue’, the
PBAC rejected the application.
3. Registration Status:
On 23 July 2004 the Therapeutic Goods Administration (TGA)-approved
indication was amended to: refractory fistulising Crohn disease -
for reducing the number of draining enterocutaneous and
rectovaginal fistulas and maintaining fistula closure. The dosage
was: induction - 5 mg/kg at weeks 0, 2 and 6; and maintenance
– 5 mg/kg every 8 weeks after induction.
Infliximab was initially TGA registered on 23 June 2000 for the
treatment of draining enterocutaneous fistulae in Crohn disease
patients. The dose was to infuse 5 mg/kg IV, followed with
additional 5 mg/kg doses administered at 2 and 6 weeks after the
first infusion.
Infliximab is also TGA registered for rheumatoid arthritis in
adults, ankylosing spondylitis, Crohn disease, psoriatic arthritis,
plaque psoriasis and ulcerative colitis.
4. Listing Requested and PBAC’s View:
The following is an abbreviation of the requested
restriction.
Section 100 listing (Highly Specialised Drugs Program)
Public and private hospital authority
required
Initial treatment of fistulising Crohn disease.
Complex fistulising Crohn disease with a draining enterocutaneous
or rectovaginal fistula.
A maximum quantity and number of repeats to provide for an initial
course of infliximab consisting of 5 doses at 5 mg per kg body
weight per dose to be administered at weeks 0, 2, 6, 14 and 22 will
be authorised.
Continuing treatment of fistulising Crohn disease.
An adequate response to infliximab treatment is defined as:
(a) closure of at least 50% in number of externally draining
fistulae or
(b) a marked reduction in drainage of all fistulae together with
less pain and induration as reported by the patient.
At the time of the authority application, medical practitioners
should request the appropriate number of vials, based on the weight
of the patient, to provide sufficient for a single infusion at a
dose of 5 mg per kg. Up to a maximum of 2 repeats will be
authorised.
For PBAC’s view see Recommendation and Reasons.
5. Clinical Place for the Proposed Therapy:
The submission claimed there are currently no other effective
therapies available for patients with this condition.
6. Comparator:
The submission nominated placebo as the main comparator on the
basis of no treatments being available for patients with complex
fistulising Crohn disease which have proven efficacy for induction
and maintenance of fistula closure. The PBAC considered this
appropriate.
7. Clinical trials
The clinical evidence for this re-submission was provided by an
indirect comparison of infliximab maintenance therapy from the
ACCENT II trial with the placebo group of the T20 trial, by means
of the common comparator arm of infliximab induction treatment. New
trial toxicity data from the ACCENT II trial were also presented in
the re-submission.
The ACCENT II trial evaluated 5 mg per kg infliximab induction plus
maintenance therapy, but all patients received infliximab induction
(the first 3 infusions) and were then randomised to maintenance
treatment every 8 weeks with infliximab or placebo. Trial T20
compared 5 mg per kg infliximab induction with placebo but there
was no maintenance therapy.
The designs of the T20 and ACCENT II trials were different and
consequently, the indirect comparison proposed by the submission
was of uncertain validity, as the infliximab induction arms were
not the randomised ‘common comparator’ and did not
represent the same patient spectrum. The T20 trial randomised
patients to infliximab or placebo for induction. All patients in
the ACCENT II trial underwent infliximab induction and then
subsequently responders and non-responders were separately
randomised to infliximab or placebo maintenance. Consequently,
there was no valid common comparator for undertaking the indirect
analysis. The eligible patients in T20 were in relapse. The
eligible patients for ACCENT II which formed the basis of this
submission were in remission.
Three reports of the studies included in the indirect comparison
published at the time of submission are as follows:
| Trial ID / First author | Protocol title / Publication title | Publication citation | |
|---|---|---|---|
| Common reference infliximab induction treatment | |||
| Infliximab | |||
| Sands BE et al (2004) | Infliximab maintenance therapy for fistulising Crohn’s disease. | Sands BE, Anderson FH, Bernstein CN, et al, NEJM
350(9):876885. NEJM 2004; 350(9): 876-885 |
|
| Sands BE et al (2004) | Long-term treatment of rectovaginal fistulas in Crohn’s disease: response to infliximab in the ACCENT II Study. | Sands BE, Blank MA, Patel K, Van Deventer SJ, Clinical Gastroenterology & Hepatology 2004, 2(10): 912-920 | |
| Placebo | |||
| Present DH et al. (1999) | Infliximab for the treatment of fistulas in patients with Crohn’s disease. | Present DH, Rutgeerts P, Targan S, et al, NEJM 1999; 340(18): 1398-1405 | |
8. Results of Trials
The primary outcomes used in the submission were not the primary
outcomes from the randomised trials. The submission claimed that
re-analysis of efficacy data was necessary to enable the use of a
more practical and objective primary efficacy outcome of response
(‘proportion in response’). The primary outcome in the
re-submission was the proportion of patients with response or
complete response (remission) at Weeks 10 and 54, derived from
re-analysis of data.
The primary outcome in the ACCENT II trial was the median time to
loss of response. The median time to loss of response was greater
than 40 weeks for the infliximab 5 mg per kg group and
statistically significantly higher compared to 14 weeks in the
placebo maintenance group (p=0.001).
The ACCENT II trial used a composite outcome to define loss of
response. A loss of fistula response occurred when a patient had a
reduction from baseline of less than 50 % in the number of draining
fistulas; or a protocol-prohibited change in Crohn disease
medication; or a surgical procedure for Crohn disease; or crossover
to increased dose; or discontinuation of study follow-up because of
lack of efficacy or loss of response.
Overall, 61 patients (62 %) in the placebo maintenance group had a
loss of response, as compared with 40 patients (42 %) in the
infliximab maintenance group. In both groups, the most common
criterion met for the loss of response was a need for a change in
the treatment of Crohn disease (38 % of the placebo maintenance
group and 25 % of the infliximab maintenance group) followed by the
recrudescence of fistulas (22 % and 16 % respectively). This 6 %
difference in the recrudescence of fistulas is the clinical outcome
of most interest. However, the treatment effect modelled in the
submission was different - using the post-hoc outcome of clinical
response at 54 weeks, the incremental difference in treatment
benefit in the economic model was 21.6 %.
The results of the primary outcome for Trial T20 showed a
significantly greater proportion of infliximab 5 mg per kg (67.7 %)
patients achieved a greater than or equal to 50 % reduction in
draining fistulae for at least 2 consecutive evaluation visits,
compared to placebo (25.8 %) patients (RR: 2.63: 95 % CI: 1.38,
5.00).
There was a significant difference in response rates of the common
comparator arms of induction treatment in ACCENT II and trial T20
given the difference in the design of the two trials. Because of
the difference, a calibration of the data was undertaken by
dividing the time-weighted average of the common arm in ACCENT II
by the time-weighted average of the common arm in T20, and applying
the calibration factor to T20 placebo data. This was used to
evaluate the clinical response and complete response (remission)
rates over time, without stopping rules, for the treatment and
comparator arms in the two key randomised trials (calibrated
submission analysis), and extrapolate the calibrated T20 placebo
and induction results using the rate of decay in response in the
ACCENT II infliximab induction and maintenance arm over the same
time period.
The PBAC was reassured however by the results of the alternative
approach undertaken during the evaluation, which better maintained
the with-in trial randomisation, to assess the treatment effect
using the trial designs without any reanalysis, and followed by
modelling the treatment effect of infliximab in series i.e.
induction (from the T20) followed by maintenance (from the ACCENT
II).
No statistically significant difference was observed between
treatment arms of the ACCENT II trial. This was expected as both
treatment arms had 3 induction doses of infliximab by week 10 and
maintenance therapy had not begun. There were a statistically
significantly greater proportion of responders in the infliximab
compared with placebo arms in Trial T20. The response rates in the
common reference arm of the two trials varied markedly (83.2 %
compared with 54.8 % in ACCENT II and T20, respectively). The
differences in the response rates for the common reference may have
indicated that important differences between the trials exist,
which are not obvious from the baseline characteristics of the
trials nor from the design of the trials and the re-submission had
not attempted to explain the differences.
The results of the indirect comparison indicated a statistically
significant difference between infliximab and placebo treated
patients (RR: 2.02; 95 % CI: 1.02, 4.02).
The effect of the calibration was to increase the response rate in
the T20 common reference arm from 54.8 % to 73.8 % (the clinical
response rate in the placebo arm was changed to 34.7 % from 25.8
%). Although closer, this remained different to the 83.2 % response
rate in the common reference arm of the ACCENT II trial. The
observed difference in the response rates to the common reference
arm in the trials may have indicated that the use of these trial
data in an indirect comparison may not be valid. The method of
calibration used to adjust these differences is also uncertain. The
calibration effectively increased the placebo response and
remission rates in Trial T20, however differences in the response
rates remained. It was unclear whether the application of a
calibration factor derived from time-weighted averages in the
common reference arms of the trials was appropriate.
The results of the indirect comparison indicated a statistically
significant difference between infliximab and placebo treated
patients (RR: 1.98; 95 % CI: 1.16, 3.38), however, a claim of
superiority based on the results of this indirect comparison is
uncertain.
The re-submission presented new toxicity data for the ACCENT II
trial. The key results are summarised below.
Summary of adverse events in the key randomised
trials
| Trial ID | Inflix 5mg/kg induction + continuous maintenance n/N (%) | Inflix 5mg/kg induction + placebo maintenance n/N (%) | RR (95% CI) |
|---|---|---|---|
| Inflix 5mg/kg n/N (%) | Placebo n/N (%) |
RR (95% CI) | |
| ACCENT II Any adverse event Serious adverse event Reasonably-related serious adverse event Adverse event leading to discontinuation Deaths Infection Treated infection Serious infection Infusion reactions |
123/138 (89.1%) 19/138 (13.8%) 3/138 (2.2%) 5/138 (3.6%) 0 73/138 (52.9%) 47/138 (34.1%) 4/138 (2.9%) 13/138 (9.4%) |
133/144 (92.4%) 33/144 (22.9%) 9/144 (6.3%) 12/144 (8.3%) 0 66/144 (45.8%) 39/144 (27.1%) 9/144 (6.3%) 4/144 (2.8%) |
0.97 (0.90, 1.04) 0.60 (0.36, 1.00) 0.35 (0.10, 1.26) 0.43 (0.16, 1.20) - 1.15 (0.91, 1.46) 1.26 (0.88, 1.79) 0.46 (0.45, 1.47) 3.39 (1.13, 10.15) |
| Trial T20 Any adverse event Serious adverse event Severe adverse event Adverse event leading to discontinuation Treated infection Infusion reactions |
20/31 (64.5%) 1/31 (3.2%) 6/31 (19.4%) 0 3/31 (9.7%) 2/31 (6.5%) |
20/31 (64.5%) 0/31 (0%) 5/31 (16.1%) 0 3/31 (9.7%) 2/31 (6.5%) |
NC 3.00 (0.13, 70.92) 1.20 (0.41, 3.52) - NC NC |
NC=not calculable
In the ACCENT II trial, the number of patients with infusion
reactions was higher in the infliximab maintenance group compared
with the placebo maintenance group (p=0.02). In trial T20, there
were no differences in adverse events between infliximab 5 mg per
kg and placebo.
The submission provided additional data on potential safety
concerns beyond those identified in the clinical trials by
providing the most recent Periodic Safety Update Report (PSUR). No
other safety evidence beyond the randomised trials was
provided.
9. Clinical Claim
The submission claimed infliximab as superior in terms of
comparative effectiveness and non-inferior in terms of comparative
safety over placebo.
The PBAC agreed that complex fistulising Crohn disease with a
draining enterocutaneous or rectovaginal fistula is a difficult
condition to treat it is chronic, and spontaneously relapsing and
remitting. Clinical evidence from both of the submitted trials
demonstrated a substantial placebo response for both induction and
maintenance treatment. The induction trial T20 shows a 26 %
response rate in the placebo arm; and the placebo response rate in
the maintenance trial (ACCENT II) for patients without a prior
response at induction was 16 % and for those patients with a prior
response at induction a response was sustained for 38 % of
patients. However patients were able to continue baseline standard
therapies.
10. Economic Analysis
An updated modelled economic evaluation was presented. The utilities used in the re-submission were derived from an Australian study
.
Cost off-sets were calculated
using resource utilisation in Jewell et al 2005 Jewell DP, Satsangi
J, Lobo A et al, 2005, Infliximab use in Crohn’s disease:
impact on health care resources in the UK, Eur J Gastroenterol
Hepatol., 17:1047−1052 and relevant diagnosis-related group
(DRG) costs from the National Hospital Cost Data Collection. The
re-submission provided analyses assuming 3, 4 or 5 induction doses
of infliximab.
The PBAC noted that the clinical evidence was presented as an
indirect comparison of infliximab maintenance therapy in the ACCENT
II trial with the placebo group of the T20 trial, via the common
comparator arm of infliximab induction treatment. The design of the
T20 and ACCENT II trials are different and consequently, the
indirect comparison proposed by the submission is of uncertain
validity, as the infliximab induction arms were not the randomised
‘common comparator’ and do not represent the same
patient spectrum. The T20 trial randomised patients to infliximab
or placebo for induction; all patients in the ACCENT II trial
underwent infliximab induction and then subsequently responders and
non-responders were separately randomised to infliximab or placebo
maintenance. Thus, the validity of the common comparator for
undertaking the indirect analysis is questionable. The eligible
patients in T20 are in relapse. The eligible patients for ACCENT II
which form the basis of this submission are both responders and
non-responders. However, the PBAC was reassured by the results of
the alternative approach, which maintained randomisation, to assess
the treatment effect using the trial designs without any
reanalysis, and then to model the treatment effect of infliximab in
series i.e. induction (from the T20) followed by maintenance (from
the ACCENT II). The results of this approach, yielded an
incremental cost per Quality Adjusted Life Year (QALY) gained in
the range of $45,000 - $75,000, which was comparable with that
claimed in the submission.
The results of the sensitivity analyses indicated that the model is
most sensitive to changes in utility values. The model was also
sensitive to hospitalisation cost offsets. The inclusion of
hospitalisation costs lowered the incremental cost-effectiveness
ratios substantially. The PBAC also noted that there was
uncertainty about the hospital and procedure costs, based on a UK
study included in the submission, which may have overestimated
costs, favouring infliximab. There was also some uncertainty about
the reliability of the Australian study used to derive utility
values as a source for utilities with and without fistula closure.
However, these uncertainties were not considered sufficient to
warrant rejection of the submission.
Details of the trial referred to above are noted in the table
below:
| Trial ID / First author | Protocol title / Publication title | Publication citation |
|---|---|---|
| Jewell DP | Infliximab use in Crohn’s disease: impact on health care resources in the UK. | Eur J Gastroenterol Hepatol; 2005: 17:1047−1052. |
11. Estimated PBS Usage and Financial Implications:
The likely number of patients per year was estimated to less than
10,000 per year in the first year of listing. The submission
estimated that the financial cost per year to the PBS minus any
savings in use of other drugs would be less than $10 million per
year for the Year 1 to Year 5 period. The PBAC noted that the
submission’s predictions of utilisation were a likely
underestimate.
12. Recommendation and Reasons:
The PBAC recommended listing as a pharmaceutical benefit of
infliximab under section 100 (Highly Specialised Drugs Program)
Public and Private Hospital Authority Required for complex
refractory fistulising Crohn disease with a draining
enterocutaneous or rectovaginal fistula, on the basis of a high,
but acceptable, cost effectiveness ratio, in the context of a
serious medical condition that has a large impact on the quality of
life of often otherwise healthy younger patients.
In terms of assessment for continuing therapy, the PBAC accepted
that response could be assessed as either closure of at least 50 %
in the number of externally draining fistulae (i.e. no drainage
despite finger pressure in at least 50 % of fistulae) or a marked
reduction in drainage of all fistulae together with less pain and
induration as reported by the patient. The PBAC did not agree to
the request for two extra doses in the initiation phase as this
would not be consistent with the doses used in the trials or the
TGA-approved dosing schedule.
The PBAC agreed that this is a difficult condition to treat - it is
chronic, and spontaneously relapsing and remitting. Clinical
evidence from both trials demonstrated a substantial placebo
response for both induction and maintenance treatment. The
induction trial T20 shows a 26 % response rate in the placebo arm;
and the placebo response rate in the maintenance trial (ACCENT II)
for patients without a prior response at induction was 16 % and for
those patients with a prior response at induction a response was
sustained for 38 % of patients.
The PBAC noted that the clinical evidence was presented as an
indirect comparison of infliximab maintenance therapy in the ACCENT
II trial with the placebo group of the T20 trial, via the common
comparator arm of infliximab induction treatment. The design of the
T20 and ACCENT II trials are different and consequently, the
indirect comparison proposed by the submission is of uncertain
validity, as the infliximab induction arms were not the randomised
‘common comparator’ and do not represent the same
patient spectrum. The T20 trial randomised patients to infliximab
or placebo for induction; all patients in the ACCENT II trial
underwent infliximab induction and then subsequently responders and
non-responders were separately randomised to infliximab or placebo
maintenance. Thus, the validity of the common comparator for
undertaking the indirect analysis is questionable. The eligible
patients in T20 are in relapse. The eligible patients for ACCENT II
which form the basis of this submission are both responders and
non-responders. However, the PBAC was reassured by the results of
the alternative approach proposed by the ESC, which maintained
randomisation, to assess the treatment effect using the trial
designs without any reanalysis, and then to model the treatment
effect of infliximab in series i.e. induction (from the T20)
followed by maintenance (from the ACCENT II). The results of this
approach yielded an incremental cost per Quality Adjusted Life Year
(QALY) gained in the range of $45,000 to $75,000, which was
comparable with that claimed in the submission.
The PBAC also noted that there was uncertainty about the hospital
and procedure costs, based on a UK study included in the
submission, which may have overestimated costs, favouring
infliximab. There was also some uncertainty about the reliability
of the Australian study used to derive utility values as a source
for utilities with and without fistula closure. However, these
uncertainties were not considered sufficient to warrant rejection
of the submission.
The PBAC noted that the submission’s predictions of
utilisation were a likely underestimate.
Recommendation:
INFLIXIMAB, powder for IV infusion, 100 mg
Extend the current restriction to include:
Section 100 listing
(Highly Specialised Drug)
Public and Private hospital authority required
To be finalised
Pack size: 1
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 welcomes the PBAC’s decision to fund infliximab for complex fistulising Crohn’s disease given the unmet clinical need for this debilitating condition. The sponsor also wishes to thank the clinical specialists for their contributions to the submission.
