Tocilizumab, concentrate for injection, 80 mg in 4 mL, 200 mg in 10 mL and 400 mg in 20 mL, Actemra® - November 2011
Page last updated: 02 March 2012
Public Summary Document
Product: Tocilizumab, concentrate for injection,
80 mg in 4 mL, 200 mg in 10 mL and 400 mg in 20 mL,
Actemra®
Sponsor: Roche Products Pty Ltd
Date of PBAC Consideration: November 2011
1. Purpose of Application
To extend the current S100 (Highly Specialised Drugs Program)
Authority Required listing to include treatment by a paediatric
rheumatologist or under the supervision of a paediatric treatment
centre, of severe active systemic juvenile idiopathic arthritis in
a patient under 18 years of age, who meets certain criteria.
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
Tocilizumab had not previously been considered by the PBAC for this
indication.
3. Registration Status
As of 4 November 2011, tocilizumab was registered by the TGA for the indications:
- Systemic Juvenile Idiopathic Arthritis: Treatment of active systemic juvenile idiopathic arthritis in patients 2 years of age and older. Tocilizumab can be given alone or in combination with methotrexate.
- Rheumatoid Arthritis: Treatment of moderate to severe active RA in adult patients: in combination with methotrexate or other non-biological DMARDs in case of either an inadequate response or intolerance to previous therapy with one or more DMARDS, or as monotherapy in case of intolerance to methotrexate or where continued treatment with methotrexate is inappropriate. Tocilizumab has been shown to inhibit the progression of joint damage, as measured by x-ray, when given in combination with methotrexate.
4. Listing Requested and PBAC’s View
The proposed amendments to the current PBS restrictions (abbreviated version) for
etanercept and adalimumab are highlighted in BOLD.
Section 100 - Highly Specialised Drugs Program
Public and Private Hospital Authority required
(Abbreviated version)
Initial 1 (new patient or patient recommencing after a break of more than 12 months)
Initial treatment by a paediatric rheumatologist, or under the supervision of a paediatric
rheumatology treatment centre, of a patient under 18 years:
a. who has severe active systemic juvenile idiopathic arthritis; AND
b. whose parent or authorised guardian has signed a patient acknowledgement; AND
c. who has not received PBS-subsidised treatment with tocilizumab for this condition in the previous 12 months; AND
d. who has demonstrated either:
i. severe intolerance of, or toxicity due to, methotrexate (see below for definition of severe intolerance and toxicity); or
ii. failure to achieve an adequate response to 1 of the following treatment regimens:
in those with polyarticular course disease, oral or parenteral methotrexate at a dose of at least 15 mg per square metre weekly, alone or in combination with oral or intra-articular corticosteroids
for a minimum of 3 months; or
in those whose disease is characterised by systemic symptoms, an inability to decrease
and maintain the dose of corticosteroids below 0.5 mg per kg per day following a minimum
of 2 months of therapy.
The following criteria indicate failure to achieve an adequate response and must be
demonstrated in all patients at the time of the initial application:
a. in those with polyarticular course disease treated with methotrexate alone or in
combination with corticosteroids:
i. an active joint count of at least 20 active (swollen and tender) joints; OR
ii. at least 4 active joints from the following list:
elbow, wrist, knee and/or ankle (assessed as swollen and tender): AND/OR
shoulder, cervical spine 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).
b. in those whose disease is characterised by systemic symptoms treated with corticosteroids:
i. an active joint count of at least 2 active joints; AND
ii. persistent fever >38ºC for at least 5 out of 14 consecutive days; AND/OR
iii. a C-reactive protein (CRP) level and platelet count above the upper limits of normal (ULN); .
A maximum of 16 weeks of treatment will be authorised under this restriction.
Initial 2 (change or re-commencement after a break of less than 12 months)
Initial PBS-subsidised treatment with tocilizumab by a paediatric rheumatologist, or under the supervision of a paediatric rheumatology
treatment centre, of a patient under 18 years who:
a. has a documented history of severe active systemic juvenile idiopathic arthritis; AND
b. in this treatment cycle, has received prior PBS-subsidised treatment with tocilizumab for this condition; AND
c. has not failed PBS-subsidised therapy with tocilizumab for this condition more than once in the current treatment cycle.
A maximum of 16 weeks of treatment will be authorised under this restriction.
Continuing treatment
Continuing PBS-subsidised treatment with tocilizumab, by a rheumatologist or under the supervision of a paediatric rheumatology treatment
centre, of a patient:
a. who has a documented history of severe active systemic juvenile idiopathic arthritis; AND
b. who has demonstrated an adequate response to treatment with tocilizumab; AND
c. whose most recent course of PBS-subsidised bDMARD treatment in this treatment cycle was with tocilizumab.
An adequate response to treatment is defined as:
a. in those with polyarticular course disease:
i. a reduction in the total active (swollen and tender) joint count by at least 50% from baseline, where baseline is at least 20 active joints; OR
ii. a reduction in the number of the following active joints, from at least 4, by at least 50%:
elbow, wrist, knee and/or ankle (assessed as swollen and tender); AND/OR
shoulder, cervical spine 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).
b. in those whose disease is characterised by systemic symptoms:
i. absence of fever in the preceding seven days; AND/OR
ii. a 30% reduction in the CRP level and platelet count; AND/OR
iii. a 30% reduction in the dose of corticosteroids.
A maximum of 24 weeks of treatment will be approved under this restriction.
The submission requested that additional wording in relation to repeat prescriptions
and assessment of response will be equivalent to that included within the current
PBS restrictions for etanercept and adalimumab for JIA.
For PBAC’s view, see Recommendation and Reasons.
5. Clinical Place for the Proposed Therapy
Juvenile idiopathic arthritis (JIA) is considered the most common
rheumatic childhood disease and is characterised by chronic joint
pain of unknown cause with symptoms persisting for more than six
weeks. Systemic JIA (sJIA) is a subset of JIA that is characterised
by the presence of arthritis with intermittent fever and rash
(systemic features).
For PBAC’s view, see Recommendation and
Reasons.
6. Comparator
The submission nominated etanercept and adalimumab as the two
comparators to tocilizumab.
For PBAC’s view, see Recommendation and
Reasons.
7. Clinical Trials
The basis of the submission was an indirect comparison of one randomised controlled trial (TENDER) comparing tocilizumab (8 mg/kg >30 kg, 12 mg/kg
<
30 kg by intra-venous (IV) infusion
every 2 weeks) with placebo in patients with sJIA and two
randomised controlled trials; (Lovell 2000) comparing etanercept
(0.4 mg/kg up to 25 mg sub-cutaneously (SC) twice weekly) with
placebo in patients with JIA and (Lovell 2008) comparing adalimumab
(24 mg/m2 SC every 2 weeks) with placebo in patients
with JIA.
The PBAC noted that there are differences between the tocilizumab
trial and the comparator trials (etanercept and adalimumab) that
affect the exchangeability of the trials for an indirect
comparison. These include the use of methotrexate disease severity,
responder status, study population and study design.
All participants in the TENDER trial had active sJIA. Only 32% of
the trial population in the etanercept trial had sJIA. The
proportion of patients with sJIA in the adalimumab trial is
unknown.
The following trials had been published at the time of
submission:
| Trial ID / First author | Protocol title / Publication title | Publication citation |
|---|---|---|
| Tocilizumab | ||
| TENDER | ||
| MRA316JP Yokota et al. (2008) | Efficacy and safety of tocilizumab in patients with systemic-onset juvenile idiopathic arthritis: a randomised, double-blind, placebo-controlled, withdrawal phase III trial. | Lancet; 2008,371:998-1006. |
| Etanercept | ||
| Lovell et al. (2000) | Etanercept in children with polyarticular juvenile rheumatoid arthritis. | N Engl J Med, 2000;342(11):763-769. |
| Adalimumab | ||
| Lovell et al. (2008) | Adalimumab with or without methotrexate in juvenile rheumatoid arthritis. | N Engl J Med, 2008;359(8):810-820. |
8. Results of Trials
The submission presented a primary analysis of the double-blind
randomised phase of the TENDER trial with the primary outcome of a
JIA American College of Rheumatology (ACR) 30 response (represents
a 30% improvement from baseline in at least 3 of 6 response
criteria without a worsening of greater than 30% in 1 remaining
response variable) and the absence of a fever.
Tocilizumab primary outcome: patients with a JIA ACR30
response and absence of fever
| Response rate parameter | Tocilizumab | Placebo (N=37) | ||
|---|---|---|---|---|
| 8 mg/kg (for patients ≥30 kg) (N=37) | 12 mg/kg (for patients <30 kg) (N=38) | All (N=75) | ||
| JIA ACR30 and absence of fever Responders (%) 95% CI for response rate | ||||
| 28 (75.7%) | 36 (94.7%) | 64 (85.3%) | 9 (24.3%) | |
| 61.9, 89.5 | 87.6, 100.0 | 77.3, 98.3 | 10.5, 38.1 | |
| Weighted difference (95% CI); p-value | 61.5% (44.9, 78.1); <0.0001 | |||
Abbreviations: JIA=juvenile idiopathic arthritis; ACR=American
College of Rheumatology; CI=confidence interval; N=number in
group
The results indicated that there was a statistically significant
improvement in the JIA ACR30 response and absence of fever at 12
weeks with tocilizumab (85.3%) compared with placebo (24.3%).
The submission presented an indirect comparison based on JIA ACR
30, 50, 70 and 90 responses between tocilizumab and both etanercept
and adalimumab.
The results for the indirect comparison of tocilizumab with or
without methotrexate (week 24) and etanercept (week 28) JIA ACR30
response rate are shown in the table below:
| Trial ID | Treatment effect RR (95% CI) | Tocilizumab n with event/N (%) | Placebo n with event/N (%) | Etanercept n with event/N (%) | Treatment effect RR (95% CI) | Indirect estimate of effect Indirect RR (95%CI) |
|---|---|---|---|---|---|---|
| TENDER | 3.89 (2.20, 6.88) | 106/112 (94.6%) | 9/37 (24.3%) | 1.68 (0.76, 3.75) | ||
| Lovell 2000 | 9/26 (34.6%) | 20/25 (80.0%) | 2.31 (1.32, 4.06) |
Abbreviations: CI=confidence interval; n=number with event;
N=number in group; RR=relative risk
The results for the indirect comparison of tocilizumab with or
without methotrexate (week 48) and adalimumab with or without
methotrexate (week 48) JIA ACR30 response rate are shown in the
following table:
| Trial ID | Treatment effect RR (95% CI) | Tocilizumab n with event/N (%) | Placebo n with event/N (%) | Adalimumab n with event/N (%) | Treatment effect RR (95% CI) | Indirect estimate of effect Indirect RR (95%CI) |
|---|---|---|---|---|---|---|
| TENDER | 3.34 (1.88, 5.94) | 91/112 (81.3%) | 9/37 (24.3%) | 1.96 (0.98, 3.92) | ||
| Lovell 2008 | 23/65 (35.4%) | 41/68 (60.3%) | 1.70 (1.16, 2.49) |
Abbreviations: CI=confidence interval; n=number with event;
N=number in group; RR=relative risk
The relative risk for tocilizumab versus etanercept is 1.68 (95%CI:
0.76, 3.75) for Paediatric ACR30 (PedACR30) and the relative risk
for tocilizumab versus adalimumab is 1.96 (95% CI: 0.98, 3.92) for
Paediatric ACR30 (PedACR30). These results indicate that there is
no statistically significant difference between tocilizumab and the
comparators.
However, the percentage of patients achieving a JIA ACR 30, 50, 70
or 90 response in the placebo (common reference) group differed
between the three trials, and the common reference groups were
completely different between the trials. In the etanercept and
adalimumab trials, the placebo group only included patients who had
initially responded to treatment with the active drug. In the
tocilizumab trial, the placebo group had received no initial prior
treatment.
For PBAC’s view on these results, see Recommendation and
Reasons.
Overall, the incidence of adverse events was higher in the
tocilizumab group compared with the placebo group (88.0% and 62.2%,
respectively). The most common adverse events were related to
infections and infestations, mainly upper respiratory tract
infection (13.3%) and nasopharyngitis (10.7%). The submission
stated that there was no statistically significant difference in
the incidence of infections and infestations with tocilizumab
compared with placebo.The submission stated that no new additional
adverse events or safety concerns were identified from the
additional data sources included in the extended assessment of
comparative safety for tocilizumab, etanercept and
adalimumab.
For PBAC’s view, see Recommendation and Reasons.
9. Clinical Claim
The submission described tocilizumab as non-inferior in terms of
comparative effectiveness and non-inferior in terms of comparative
safety over etanercept and adalimumab.
The PBAC accepted the submission’s claim of non-inferiority
of tocilizumab in terms of comparative effectiveness over
etanercept and adalimumab. The PBAC considered that tocilizumab has
a greater risk of adverse events compared with placebo and a
different risk of adverse events compared with etanercept and
adalimumab.
10. Economic Analysis
The submission presented a cost minimisation analysis.
The equi-effective doses are, tocilizumab: <30 kg 12 mg/kg and
≥30 kg 8 mg/kg administered by 60 minute IV infusion every 2
weeks compared with etanercept: 0.4 mg/kg up to 25mg SC twice
weekly, estimated using the weight distribution from the TENDER
trial.
For PBAC’s view, see Recommendation and Reasons.
11. Estimated PBS Usage and Financial Implications
The likely number of patients treated was estimated by the
submission to be less than 10,000 over the first 5 years. The
estimate was uncertain.
The submission estimated there would be net financial savings to
the PBS.
12. Recommendation and Reasons
The PBAC recommended listing tocilizumab on the PBS in the Section
100 (Highly Specialised Drugs Program) as a Public and Private
Hospital Authority Required benefit on a cost minimisation basis
compared with etanercept and adalimumab. The equi-effective doses
estimated using the weight distribution from the TENDER trial are,
tocilizumab: <30kg 12mg/kg and ≥30kg 8mg/kg administered by
60 minute IV infusion every 2 weeks compared with etanercept:
0.4mg/kg up to 25mg SC twice weekly and adalimumab 24
mg/m2 SC every two weeks (Lovell 2008 trial).
The PBAC noted that JIA is a heterogeneous disease in which
inflammatory arthritis may involve many or a few joints plus fever.
It has a complex disease classification and may run a variable
course including a polycyclic course characterised by flare-ups in
systemic activity (sJIA). Systemic JIA is an uncommon, serious and
potential crippling disease associated with a notable morbidity
risk. The PBAC agreed with the advice of the Paediatric Medicines
Advisory Committee (PMAG) that there was a high clinical need for
tocilizumab for use in the treatment of children who currently have
very limited effective PBS-subsidised treatment options for
sJIA.
The PBAC agreed that the comparators etanercept and adalimumab are
appropriate for patients with polyarticular joint involvement. The
PBAC considered that tocilizumab would be used as an alternative to
etanercept and adalimumab in this population group. However,
etanercept and adalimumab are not currently TGA-approved or
PBS-listed for use in sJIA. The PBAC therefore agreed that separate
systemic JIA (sJIA) and polyarticular JIA (PaJIA) listings are
appropriate. The PBAC noted that finalisation of the restriction
wording will require input from the Department, relevant sponsors,
Medicare PMAG and specialist paediatric rheumatologists regarding
interchangeability criteria and appropriate criteria for use in
patients with systemic JIA.
The PBAC noted that no head-to-head studies comparing tocilizumab
with the two TNF-alpha inhibitors (bDMARDs) in paediatric sJIA
patients are available. The basis of the submission was an indirect
comparison of the TENDER randomised controlled trial (RCT) of
tocilizumab (8 or 12mg per kg intravenously every two weeks) versus
placebo in patients with sJIA, a RCT (Lovell 2000) of etanercept
(0.4 mg per kg up to 25 mg SC twice weekly) versus placebo in
patients with JIA and sJIA, and a third RCT (Lovell 2008) comparing
adalimumab (24 mg/m2 second weekly) versus placebo in
patients with JIA based on the common comparator placebo. The
indirect comparison was based on the ACR30 response rates with
placebo as the common reference.
The PBAC noted that the comparative effectiveness of tocilizumab is
difficult to assess in the absence of head-to-head data. The
results of the placebo-controlled RCTs, taken separately, suggest
that tocilizumab has similar effectiveness to the comparators.
However, the study designs are different and patients enrolled in
the trials are different and not wholly representative of those for
whom listing is sought and the validity of the combined indirect
comparison is therefore questionable.
The PBAC noted that the comparative safety of tocilizumab is
difficult to assess in the absence of head-to head trial data and
this limits the conclusions that may be drawn from the available
evidence. The PBAC noted however that tocilizumab has a greater
risk of adverse events compared with placebo, and reported side
effects included increased risk of infection and elevated lipid
levels. In addition, infusion and anaphylactic reactions can occur.
The PBAC acknowledged the unknown risks associated with the use of
biologic agents in children. The PBAC noted that as a
PBS-subsidised HSD, tocilizumab will be managed by specialist
physicians and be supplied through public and private hospitals
that have appropriate specialist facilities. The PBAC agreed that
this is appropriate as the long-term safety profile of tocilizumab
in sJIA is being established.
The PBAC also noted the TGA recommendation that infusion of
tocilizumab for this indication should take place in a hospital
until there is adequate demonstration of safety of administration
in sufficiently large numbers of children. The PBAC considered that
paediatric patients receiving tocilizumab will most likely be
treated in a public rather than a private hospital setting given
the requirement for intravenous administration and that short stay
admission into hospital may be needed. The PBAC further noted that
the process of administering intravenous infusions for children may
be difficult and the submission’s estimated MBS
administration cost for intravenous infusions is underestimated.
The full costs will vary greatly for a small child compared to an
adolescent, as a small child will require closer monitoring and
supervision and possibly sedation and anaesthesia for the insertion
of the IV cannula. The PBAC also noted that an admitted patient
(inpatient) would not be eligible for PBS-subsidisation under
Section 100 HSD funding arrangements.
The PBAC accepted the submission’s claim of non-inferiority
of tocilizumab in terms of comparative effectiveness over
etanercept and adalimumab. The PBAC considered that tocilizumab has
a greater risk of adverse events compared with placebo and a
different risk of adverse events compared with etanercept and
adalimumab.
The PBAC requested that when available, the sponsor provide the
PBAC with the outcomes of the European-based double-blind CHARISMA
RCT trial that is investigating the safety and efficacy of repeat
infusions of tocilizumab alone and in combination with methotrexate
for the treatment of rheumatoid arthritis.
Recommendation:
TOCILIZUMAB, concentrate for injection, 80 mg in 4 mL, 200 mg in 10
mL and 400 mg in 20 mL
Extend the current restriction to include:
Restriction: To be finalised
Section 100 Highly Specialised Drugs Program
Public and Private Hospital Authority
Required
Maximum qty: 1 (all strengths)
Rpt: Nil
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.
