Certolizumab Pegol, injection, 200 mg in 1 mL, single use pre-filled syringe, Cimzia® - March 2010
Public Summary Document for Certolizumab Pegol, injection, 200 mg in 1 mL, single use pre-filled syringe, Cimzia® - March 2010
Page last updated: 02 July 2010
Public Summary Document
Product: CERTOLIZUMAB PEGOL, injection, 200 mg in
1 mL, single use pre- filled syringe, Cimzia®
Sponsor: UCB Australia Pty Ltd
Date of PBAC Consideration: March 2010
1. Purpose of Application
The submission sought an Authority required listing for the
treatment of severe active rheumatoid arthritis in adult patients
who meet certain criteria.
2. Background
This drug had not previously been considered by the PBAC.
3. Registration Status
Certolizumab was registered with the Therapeutic Goods Administration (TGA) on 22 December 2009 for the treatment of moderate to severe active rheumatoid arthritis in adult patients,
- combined with methotrexate in case of either an inadequate response or intolerance to previous therapy with one or more disease-modifying antirheumatic drugs (DMARDS), or
- as monotherapy in case of a contraindication or intolerance to methotrexate
4. Listing Requested and PBAC’s View
The following is an abbreviated version of the listing requested:
Authority Required
Initial 1 (new patients)
Application for initial PBS-subsidised treatment with certolizumab pegol, by a rheumatologist
or clinical immunologist with expertise in the management of rheumatoid arthritis,
of adults who:
a) have severe active rheumatoid arthritis; and
b) have received no prior PBS-subsidised treatment with a bDMARD for this condition
in this treatment cycle; and
c) have failed to achieve an adequate response to the following treatments:
i. methotrexate at a dose of at least 20 mg weekly; and
ii. methotrexate (at a minimum dose of 7.5 mg weekly), in combination with 2 other non-biological disease modifying anti-rheumatic drugs (DMARDs), for a minimum of 3 months; and
iii. a minimum of 3 months' treatment with:
1. leflunomide alone; or
2. leflunomide in combination with methotrexate; or
3. cyclosporin.
The following initiation criteria indicate failure to achieve an adequate response
and must be demonstrated in all patients at the time of the initial application:
1. an elevated erythrocyte sedimentation rate (ESR) greater than 25 mm per hour or
a C-reactive protein (CRP) level greater than 15 mg per L;
AND either
2. a total active joint count of at least 20 active (swollen and tender) joints; or
3. at least 4 active joints from the following list of major joints:
• elbow, wrist, knee and/or ankle (assessed as swollen and tender); and/or
• shoulder and/or hip (assessed as pain in passive movement and restriction of passive movement, where pain and limitation of movement are due to active disease and not irreversible damage such as joint destruction or bony overgrowth).
All tests and assessments should be performed preferably whilst still on treatment,
but no longer than 1 month following cessation of the most recent prior treatment.
Assessment of a patient's response to an initial course of treatment must be made
after at least 12 weeks of treatment so that there is adequate time for a response
to be demonstrated. This assessment, which will be used to determine eligibility for
continuing treatment, must be submitted to Medicare Australia no later than 1 month
from the date of completion of this initial course of treatment. Where a response
assessment is not undertaken and submitted to Medicare Australia within these timeframes,
the patient will be deemed to have failed to respond to treatment with certolizumab
pegol.
Authority Required
Continuing treatment
Following the completion of an initial treatment course with a specific bDMARD, a
patient may qualify to receive up to 24 weeks of continuing treatment with that drug
providing they have demonstrated an adequate response to treatment. The patient remains
eligible to receive continuing bDMARD treatment with the same drug in courses of up
to 24 weeks providing they continue to sustain the response.
It is recommended that a patient be reviewed in the month prior to completing their
current course of treatment to ensure uninterrupted bDMARD supply.
Assessments of response to a course of PBS-subsidised therapy must be submitted to
Medicare Australia no later than 4 weeks from the date that course was ceased.
Where a response assessment is not submitted to Medicare Australia within these timeframes,
the patient will be deemed to have failed to respond to treatment with that bDMARD.
The PBAC considered that the requested restriction and interchangeability criteria
for certolizumab should be identical to those of adalimumab but would also need to
incorporate the changes recommended at the December 2009 special PBAC meeting for
all PBS listed biological disease modifying anti-rheumatic drugs (bDMARDs) for rheumatoid
arthritis. See Recommendation and Reasons.
5. Clinical place for the proposed therapy
Rheumatoid arthritis is an inflammatory disorder, typically
featuring a combination of peripheral symmetrical inflammatory
arthritis and a number of well-described extra-articular symptoms.
It is associated with significant morbidity, disability and
mortality.
Certolizumab would provide another bDMARD treatment option for
adult patients with severe active rheumatoid arthritis.
6. Comparator
The submission nominated adalimumab as the main comparator. The
PBAC accepted that this was an appropriate comparator.
7. Clinical Trials
The submission presented an indirect comparison of certolizumab
(given in combination with methotrexate) with adalimumab (given in
combination with methotrexate) based on six randomised comparative
trials using placebo as the common comparator. Five of these six
trials had been published at the time of submission, as shown in
the table below. An indirect comparison in the monotherapy setting
(certolizumab or adalimumab given alone) was also presented and was
based on three randomised comparative trials using placebo as the
common comparator.
The published trials presented in the submission are shown as
follows:
| Trial ID / First author | Protocol title / Publication title | Publication citation |
|---|---|---|
| With methotrexate | ||
| Adalimumab plus methotrexate | ||
| Monotherapy | ||
| CPD870-027 (RA-I Rapid1) Keystone et al. (2008) |
CDP870-027 Certolizumab pegol plus methotrexate is significantly more effective than placebo plus methotrexate in active rheumatoid arthritis. |
October 2007 Arthritis & Rheumatism 2008, 58(11): 3319-3329. |
| CDP870-050 (RA-II: Rapid2) Smolen et al. (2008) |
CDP870-050 Efficacy and safety of certolizumab pegol plus methotrexate in active rheumatoid arthritis: the RAPID 2 study. A randomized control trial. |
October 2007 Ann Rheum Dis doi: 2008, 10.1136(2009; 68(6): 797-804) |
| Weinblatt et al. (2003) | Adalimumab, a fully human anti-tumor necrosis factor a monoclonal antibody, for the treatment of rheumatoid arthritis in patients taking concomitant methotrexate: The ARMADA trial. | Arthritis Rheum 48(1): 35-45. |
| Keystone et al. (2004) | Radiographic, clinical and functional outcomes of treatment with adalimumab (a human anti-tumor necrosis factor monoclonal antibody) in patients with active rheumatoid arthritis receiving concomitant methotrexate therapy. | Arthritis Rheum 2004, 50(5): 1400-1411 |
| Kim et al. (2007) | A randomized, double-blind, placebo-controlled, phase III study of the human anti-tumor necrosis factor antibody adalimumab administered sub-cutaneous injections in Korean rheumatoid arthritis patients treated with methotrexate. | Journal of Rheumatology 2007, 10:9-16 |
| CDP870-011 (RA-III FAST4WARD) Fleischmann et al. (2009) |
CDP870-011 Efficacy and safety of certolizumab pegol monotherapy every 4 weeks in patients with rheumatoid arthritis failing previous disease-modifying antirheumatic therapy: the FAST 4WARD study. |
July 2006 Ann Rheum Dis 2009, 686 805-811 |
| Van de Putte et al. (2004) | Efficacy and safety of adalimumab as monotherapy in patients with rheumatoid arthritis for whom previous disease modifying antirheumatic drug treatment has failed. | Ann Rheum Dis 2004, 63(5): 508-516 |
| Miyasaka et al. (2008) | Clinical investigation in highly disease-affected rheumatoid arthritis patients in Japan with adalimumab applying standard and general evaluation: the CHANGE study | Mod Rheumatol 2008, 18252-262 |
8. Results of Trials
The submission presented indirect comparisons using the American College of Rheumatology
(ACR) 20/50/70 responses at 12, 14/16 and 24/26 weeks as the measure of outcome, and
the indirect odds ratio (OR), relative risk (RR) and risk difference (RD) as the analytical
measures. The submission nominated the indirect OR as the preferred analytical measure
and 12 weeks as the preferred endpoint.
At the submission’s preferred time point of 12 weeks, all indirect comparisons showed
no statistically significant difference between certolizumab and adalimumab for either
dosage regimen in the plus methotrexate setting, or in the monotherapy setting.
There was also no statistically significant difference at 14/16 weeks and 24 weeks,
for the certolizumab 200 mg given once every 2 weeks (Q2W) (after loading doses) plus
methotrexate regimen. However, for the certolizumab 400 mg given once every 4 weeks
(Q4W) plus methotrexate regimen at 24 weeks, statistically significant differences
favouring adalimumab were observed for the ACR70 based on the indirect OR (and RR,
RD); for the ACR50 based on the indirect RR and RD; and for the ACR20 based on the
indirect RD. In addition, there was a non-significant trend favouring adalimumab for
some of the measures/time points.
For the certolizumab 400 mg Q4W monotherapy regimen, a statistically significant difference
favouring adalimumab was observed in ACR70 response at 14/16 weeks for the indirect
RD (-0.071 95 % CI -0.131, -0.011).
The submission also presented a number of backward step indirect comparisons, excluding
some of the trials with less comparable characteristics (one certolizumab trial with
a lower mean methotrexate dose (i.e. CDP870-050) and/or two adalimumab trials undertaken
in Asian populations (i.e. Kim et al. 2007, Miyasaka et al. 2008). For the certolizumab
200 mg Q2W (after loading) plus methotrexate regimen, the backward step analysis excluding
Kim et al. (2007) showed a statistically significant difference favouring certolizumab
based on the indirect OR (and indirect RR, RD) for the ACR20 at 12 weeks. No statistically
significant differences were observed in an analysis excluding Kim et al. (2007) and
CDP870-050.
For the certolizumab 400 mg Q4W monotherapy regimen, the backward step analysis excluding
Miyasaka et al. (2008) exhibited five statistically significant differences (two favouring
certolizumab and three favouring adalimumab – including two favouring adalimumab at
the submission’s preferred 12 week time point). However, none were based on the submission’s
preferred analytical measure of the indirect OR.
The PBAC noted that the only certolizumab trials that were consistent with the TGA
recommended doses were trials CDP870-027 and CDP870-050 which used a 400 mg loading
doses at 0, 2 and 4 weeks followed by 200 mg every two weeks and where methotrexate
was given concomitantly. On the totality of the evidence, the PBAC accepted that certolizumab
plus methotrexate and as monotherapy was non inferior to adalimumab in terms of comparative
effectiveness at the recommended TGA dose (400 mg loading dose with a 200 mg biweekly
or 400 mg four weekly maintenance dose).
The submission did not provide any comparison from the clinical trials (as an indirect
analysis or as a descriptive summary) of safety outcomes for certolizumab versus adalimumab.
This did not permit any assessment of the comparative safety of certolizumab to be
made. The submission addressed an extended assessment of safety using information
from three open-label extension studies of certolizumab, a Periodic Safety Update
report for certolizumab, an integrated safety report for certolizumab, an open label
extension study for adalimumab, and the relevant Product Information (PI). The submission
concluded that the pattern and incidence of adverse events with certolizumab is consistent
with that observed in rheumatoid arthritis RA patients treated with other tumour necrosis
factor (TNF) inhibitor therapy.
The PBAC noted that while no formal indirect comparisons of adverse event data for
certolizumab and adalimumab was presented in the submission, the sponsor in its pre-PBAC
advice provided an indirect comparison of key safety outcomes based on absolute numbers
which indicated that there was no evidence of differences in the pattern and incidence
of adverse events in rheumatoid arthritis patients treated with certolizumab to currently
listed anti TNF agents.
9. Clinical Claim
The submission described certolizumab as non-inferior to adalimumab
in terms of comparative effectiveness.
On the totality of the evidence, the PBAC accepted that
certolizumab plus methotrexate and as monotherapy was non inferior
to adalimumab in terms of comparative effectiveness at the
recommended TGA dose (400 mg loading dose with a 200 mg biweekly or
400 mg four weekly maintenance dose).
10. Economic Analysis
The submission presented a single cost-minimisation analysis to
cover both the plus methotrexate and monotherapy settings, based on
a certolizumab dose of 400 mg at weeks 0, 2 and 4 followed by 200
mg Q2W (or 400 mg Q4W). The use of (i) a loading dose with a 400 mg
Q4W regimen, in either the plus methotrexate or in the monotherapy
setting; or (ii) a 200 mg Q2W regimen in the monotherapy setting,
were not consistent with the clinical evidence presented by the
submission.
The submission estimated no incremental cost associated with
certolizumab (undiscounted estimate over 2 years assuming 67 %
continuation rate). The proportion of responders of 67 % was not
clearly justified by the submission. Further, during evaluation it
became apparent that the submission under-estimated the usage of
certolizumab in the continuation phase by 0.5 scripts. Thus the
submission’s analysis was likely to have underestimated the
costs associated with certolizumab treatment.
11. Estimated PBS Usage and Financial Implications
The likely number of prescriptions dispensed/year was estimated to
be less than 10,000 initiation scripts per year and between 10,000
to 50,000 continuation scripts per year in Year 5.
The financial cost/year to the PBS was estimated to be less than
$10 million in Year 5. The estimate was based on 12.5 continuation
scripts per year in Year 2 of treatment and onwards. Amendment to
13 continuation scripts in Year 2 of treatment onwards resulted in
an estimated cost to the PBS of also less than $10 million per year
in Year 5.
12. Recommendation and Reasons:
The PBAC recommended the listing of certolizumab on the PBS as an Authority required benefit for the treatment of rheumatoid arthritis in combination with methotrexate and as monotherapy where there is a contraindication or intolerance to methotrexate on a cost minimisation basis with adalimumab on drug costs alone. The equi-effective doses are certolizumab 400 mg at weeks 0, 2, 4 followed by 200 mg every 2 weeks or 400 mg every 4 weeks and adalimumab 40 mg administered every 2 weeks.
The submission presented an indirect comparison via placebo of certolizumab and adalimumab
with and without methotrexate. The PBAC noted that the only certolizumab trials that
were consistent with the TGA recommended doses were trials CDP870-027 and CDP870-050
which used a 400 mg loading doses at 0, 2 and 4 weeks followed by 200 mg every two
weeks and where methotrexate was given concomitantly. On the totality of the evidence,
the PBAC accepted that certolizumab plus methotrexate and as monotherapy was non inferior
to adalimumab in terms of comparative effectiveness at the recommended TGA dose (400
mg loading dose with a 200 mg biweekly or 400 mg four weekly maintenance dose).
The PBAC noted that while no formal indirect comparisons of adverse event data for
certolizumab and adalimumab was presented in the submission, the sponsor in its pre-PBAC
advice provided an indirect comparison of key safety outcomes based on absolute numbers
which indicated that there was no evidence of differences in the pattern and incidence
of adverse events in rheumatoid arthritis patients treated with certolizumab to currently
listed anti TNF agents.
The PBAC considered that the requested restriction and interchangeability criteria
for certolizumab should be identical to those of adalimumab but would also need to
incorporate the changes recommended at the December 2009 special PBAC meeting for
all PBS listed bDMARDs for rheumatoid arthritis.
Recommendation:
CERTOLIZUMAB PEGOL, injection, 200 mg in 1 mL single use pre-filled syringe
Restriction: Authority Required
To be finalised
Maximum quantity: 2
Repeats: 2 (Initiation), 5 (continuing)
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
UCB welcomes the decision of the PBAC to make Cimzia (certolizumab pegol) available as a treatment option for patients living with rheumatoid arthritis.
