Adalimumab, injection, 20 mg in 0.4 mL, 40 mg in 0.8 mL, pre-filled syringe, Humira® - March 2010
Public Summary Document for Adalimumab, injection, 20 mg in 0.4 mL, 40 mg in 0.8 mL, pre-filled syringe, Humira® - March 2010
Page last updated: 02 July 2010
Public Summary Document
Product: ADALIMUMAB, injection, 20 mg in 0.4 mL,
40 mg in 0.8 mL, pre- filled syringe, Humira®
Sponsor: Abbott Australasia Pty Ltd
Date of PBAC Consideration: March 2010
1. Purpose of Application
The submission sought a Section 100 (Highly Specialised Drugs
Program) listing for the treatment of severe active polyarticular
course juvenile chronic arthritis.
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
This drug had not previously been considered by the PBAC for this
indication.
Adalimumab is currently listed on the Pharmaceutical Benefits
Scheme (PBS) for the treatment of rheumatoid arthritis, psoriatic
arthritis, ankylosing spondylitis, severe refractory Crohn disease
and chronic plaque psoriasis.
3. Registration Status
Adalimumab was registered by the Therapeutic Goods Administration
(TGA) on 2 July 2009 for use in combination with methotrexate for
reducing the signs and symptoms of moderately to severely active
polyarticular juvenile idiopathic arthritis in patients aged 4
years of age and older. Adalimumab can be given as monotherapy in
case of intolerance or when continued treatment with methotrexate
is inappropriate.
Adalimumab is also TGA registered for:
- Rheumatoid Arthritis
- Psoriatic Arthritis
- Ankylosing Spondylitis
- Crohn Disease
- Psoriasis
4. Listing Requested and PBAC’s View
The following is an abbreviation of the requested restriction.
It is not a complete restriction.
Public and private hospital authority
required
Initial treatment by a paediatric rheumatologist, or under the
supervision of a paediatric rheumatology treatment centre, of
patients under 18 years who have severe active polyarticular course
juvenile chronic arthritis; AND
(a) whose parent or authorised guardian has signed a patient
agreement form indicating that they understand and acknowledge that
PBS-subsidised treatment will cease if the predetermined response
criteria do not support continuation of PBS-subsidised treatment;
AND
(b) who have 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 or more of the
following treatment regimens:
— oral or parenteral methotrexate at a dose of at least 20 mg
per square metre weekly, alone or in combination with oral or
intra-articular corticosteroids, for a minimum of 3 months;
or
— oral methotrexate at a dose of at least 10 mg per square
metre weekly together with at least 1 other DMARD, alone or in
combination with corticosteroids, for a minimum of 3 months. (Note:
use of alternative DMARDs in children is dependent on approval by
the Therapeutic Goods Administration as age restrictions may
apply).
Public and private hospital authority
required
Initial PBS-subsidised supply for continuing treatment by a
rheumatologist, or under the supervision of a paediatric
rheumatology treatment centre, of severe active polyarticular
course juvenile chronic arthritis in patients
(a) whose parent or authorised guardian has signed a patient
agreement form indicating that they understand and acknowledge that
PBS-subsidised treatment will cease if the predetermined response
criteria do not support continuation of PBS-subsidised treatment;
AND
(b) who have demonstrated a response as specified in the criteria
for continuing PBS-subsidised treatment with adalimumab.
Public and private hospital authority
required
Continuing PBS-subsidised treatment by a rheumatologist, or under
the supervision of a paediatric rheumatology treatment centre, of
severe active polyarticular course juvenile chronic arthritis in
patients who have demonstrated an adequate response to treatment
with adalimumab as manifested by:
(a) an active joint count of fewer than 10 active (swollen and
tender) joints; OR
(b) a reduction in the active (swollen and tender) joint count by
at least 50 % from baseline; OR
(c) a reduction in the number of the following active joints, from
at least 4, by at least 50 %:
(i) elbow, wrist, knee and/or ankle (assessed as swollen and
tender); and/or
(ii) 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).
Continuing PBS-subsidised treatment by a rheumatologist, or under
the supervision of a paediatric rheumatology treatment centre, of
severe active polyarticular course juvenile chronic arthritis in
patients 18 years or older who have demonstrated an adequate
response to treatment with adalimumab as manifested by:
(a) an active joint count of fewer than 10 active (swollen and
tender) joints; OR
(b) a reduction in the active (swollen and tender) joint count by
at least 50 % from baseline; OR
(c) a reduction in the number of the following active joints, from
at least 4, by at least 50 %:
(i) elbow, wrist, knee and/or ankle (assessed as swollen and
tender); and/or
(ii) 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).
The PBAC noted that the efficacy of adalimumab is superior when
used in combination with methotrexate and clinicians would
therefore use it in this combination whenever possible. The
Committee therefore did not consider that the requested restriction
should be amended to explicitly require adalimumab to be used in
combination with methotrexate in patients who are able to tolerate
methotrexate. The Committee agreed that the restriction should
allow interchangeability with etanercept and allow a total of three
attempts (two of one of either adalimumab or etanercept and one of
the other).
5. Clinical Place for the Proposed Therapy
Juvenile idiopathic arthritis (JIA) is the most common rheumatic
disease of childhood, defined as persistent arthritis for more than
6 weeks with an onset at less than 16 years of age, after excluding
other causes. The term JIA represents several different sub-types
of arthritis. Current treatment includes non-pharmacological
interventions, analgesics, non-steroidal anti-inflammatory drugs
(NSAIDs), corticosteroids, disease modifying anti-rheumatic drugs
(DMARDs) and biological disease modifying anti-rheumatic drugs
(bDMARDs).
Adalimumab would provide clinicians with an alternative bDMARD
therapy for patients with JIA.
6. Comparator
The submission nominated etanercept as the main comparator. The
main argument provided in support of this nomination is that
etanercept is the only bDMARD listed on the PBS for the treatment
of JIA. This was considered appropriate.
7. Clinical Trials
The basis of the submission was an indirect comparison of one
randomised trial (DE038) comparing adalimumab (24 mg/m2
sub-cutaneously once every second week) with placebo and one
randomised trial (Lovell et al. 2000) comparing etanercept (0.4
mg/kg up to 25 mg sub-cutaneously twice weekly) with placebo in
patients with JIA. The inclusion and exclusion criteria were
generally comparable between the adalimumab and etanercept trials
except for one important difference. It was noted that Lovell et
al. (2000) required patients to demonstrate active disease despite
the use of NSAIDs and methotrexate (MTX), whereas DE038 enrolled
patients with active disease despite the use of NSAIDs with or
without concomitant MTX. The patients enrolled in DE038 therefore
included those either naive to MTX, intolerant to MTX or those with
an inadequate response to MTX who may or may not have ceased
MTX.
Both the Lovell et al. (2000) and the DE038 trials were withdrawal
trials in design, with open label lead-in phases of 12 weeks and 16
weeks (with additional assessment at 12 weeks) for etanercept and
adalimumab, respectively. Only responders were randomised
(double-blind) to treatment after the lead-in phase, which was 16
weeks for etanercept and 32 weeks (with additional assessment at 16
weeks) for adalimumab.
The published trials presented in the submission are shown
below:
| Trial ID / First author | Protocol title / Publication title | Publication citation |
|---|---|---|
| DE038 | ||
| Lovell et al. (2000) | ||
| Lovell et al. (2008b)* Ruperto et al. (2006) |
Adalimumab with or without methotrexate in juvenile
rheumatoid arthritis. 48-week data from the study of adalimumab in children with juvenile idiopathic arthritis (JIA). |
New Engl J Med 2008; 359(8):810-820 Annals of the Rheumatic Diseases 2006; 65(Suppl II):56. |
| Lovell et al. (2000) Lovell et al. (2003) Lovell et al. (2006) Lovell et al. (2008a)* |
Etanercept in children with polyarticular juvenile
rheumatoid arthritis. 2 year extension data: Lovell et al. Long term efficacy and safety of etanercept in children with polyarticular-course juvenile rheumatoid arthritis. 4 year extension data: Lovell et al. Long term safety and efficacy of etanercept in children with polyarticular-course juvenile rheumatoid arthritis. 8 year extension data: Lovell et al. Safety and efficacy of up to eight years of continuous etanercept therapy in patients with juvenile rheumatoid arthritis. |
NEJM 2000;342:763 Arthritis & Rheumatism 2003; 48:218-226 Arthritis & Rheumatism 2006; 54:1987-1994. Arthritis & Rheumatism 2008; 58:1496 |
* to distinguish the two citations by Lovell in 2008, the
citation referring to adalimumab is referred to as Lovell et al
2008b, and etanercept citation as Lovell et al 2008a.
The PBAC agreed that the patients enrolled in the adalimumab trial
were not wholly representative of those for whom listing is sought
as the submission estimated that less than 50 % of patients from
Trial DE038 would qualify for adalimumab treatment on PBS. However,
it was also noted that the design of the trials for the etanercept
submission considered in December 2002 were similar and would have
had a similar issue with applicability of the trial
population.
8. Results of Trials
The submission presented the results of the Paediatric American College of Rheumatology (PedACR) responses observed for adalimumab and etanercept in the open-label-lead-in (OLLI) phases of the respective trials, followed by the results of indirect comparisons between adalimumab and etanercept monotherapy in the double-blind (DB) phases using placebo as a common reference for the outcomes:
- Proportion of patients with disease flare in the double blind phase, and
- Proportion of patients with PedACR30/50/70 response in the double blind phase.
Adalimumab: Trial DE038
The following table presents the proportions of patients achieving a Paediatric American
College of Rheumatology (PedACR) 30/50/70 responseat 16 weeks (during the open label
phase) for adalimumab. Patients with a PedACR 30 response at week 16 were eligible
for double-blind treatment.
The proportion of patients with PedACR response at the end of the OLLI phase (16 weeks)
are presented in the following table:
| DE038 | ||
|---|---|---|
| ADA (MTX stratum) n/N (%) (at week 16) | ADA (non-MTX stratum) n/N (%) (at week 16) | |
| PedACR30 | 80/85 (94.1%) | 64/86 (74.4%) |
| PedACR50 | 77/85 (90.6%) | 55/86 (64%) |
| PedACR70 | 60/85 (70.6%) | 40/86 (46.5%) |
In the double-blind phase, disease flares, which were the primary endpoint, were statistically
significantly lower among patients receiving adalimumab (both with and without MTX)
than those receiving placebo. In the treatment arm without MTX the number of patients
with disease flares were 13 of 30 for patients who received adalimumab (43 %) vs.
20 of 28 for patients who received placebo (71 %), (P = 0.03). In the treatment arm
with MTX use the number of patients with disease flares were 14 of 38 for patients
who received adalimumab (37 %) and 24 of 37 for patients who received placebo (65
%) (P = 0.02).
PedACR 30, 50, 70 and 90 responses for the 32 week double-blind phase (week 48) are
presented in the table below. Statistically significant differences from placebo were
observed for PedACR 30, 50 and 70 in the adalimumab plus methotrexate arm.
| PedACR response | No Methotrexate | Methotrexate | ||||
|---|---|---|---|---|---|---|
| Placebo (N=28) | Adalimumab (N=30) | P-value | Placebo (N= 37) | Adalimumab (N= 38) | P-value | |
| 30 | 9 (32%) | 17 (57%) | 0.06 | 14 (38%) | 24 (63%) | 0.03 |
| 50 | 9 (32%) | 16 (53%) | 0.10 | 14 (38%) | 24 (63%) | 0.03 |
| 70 | 8 (29%) | 14 (47%) | 0.16 | 10 (27%) | 24 (63%) | 0.002 |
| 90 | 5 (18%) | 9 (30%) | 0.28 | 10 (27%) | 16 (42%) | 0.17 |
Indirect Comparison
Although the estimates of the proportions of patients achieving PedACR 30 and 50 at
week 12 (during the open label phase) when treated with adalimumab without methotrexate
or etanercept were similar, the absence of a common reference limited the meaningfulness
of the comparison, particularly given the differences in the baseline characteristics
of patients in the adalimumab and etanercept trials. The addition of methotrexate
to adalimumab improved response rates as determined by PedACR30, 50 and 70 and was
the rationale behind the TGA indication requiring combination use of adalimumab and
MTX, unless patients are intolerant to MTX or continued treatment is no longer appropriate.
Although these results were non-comparative and there were no statistical analyses
available, the open-label lead-in phases showed a high and comparable PedACR response
between adalimumab and etanercept. Combination use with MTX improved the response.
Due to both the adalimumab and etanercept trials being withdrawal trials in design,
the outcome compared in the indirect comparisons was the proportion of patients experiencing
disease flares. As acknowledged by the submission, the outcome was difficult to interpret
and essentially measured the relapse rates of ACR30 responders who continue with active
treatment compared with those who switch to placebo.
The table below summarises the proportion of patients who had a disease flare at the
end of the double blind phase (32 weeks for adalimumab and 16 weeks for etanercept).
The table below presents the comparison of the adalimumab non-MTX stratum arm and
etanercept. Similar results were observed for the comparison of the adalimumab with
MTX stratum arm and etanercept.
| Trial | Treatment effect a RR [95% CI] | ADA (non MTX) n/N (%) | PLA n/N (%) | ETN n/N (%) | Treatment effect b RR (95% CI) | Indirect RR c (95% CI) |
|---|---|---|---|---|---|---|
| End of the DB phase (ADA = 32 weeks; ETN = 16 weeks) | ||||||
| Lovell (2000) | - | - | 21/26 (80.8) |
7/25 (28.0) |
0.35 [0.18,0.67] | |
| DE038 | 0.61 [0.38,0.97] | 13/30 (43.3) |
20/28 (71.4) |
- | - | 1.75 [0.78,3.93] |
Abbreviations: CI=confidence interval; n = number with event; N = number in group;
RR=relative risk; DB=double blind
a proposed drug over common reference
b main comparator over common reference
c inferred as proposed drug over main comparator
Bolded typography indicates statistically significant differences
The PBAC noted that the efficacy of adalimumab is superior when used in combination
with methotrexate and clinicians would therefore use it in this combination whenever
possible. As acknowledged by the submission, there were differences in baseline characteristics,
concomitant background medication and different time periods of comparisons, although
the withdrawal design of the trials was similar.
Overall there were no statistically significant differences in the rates of adverse
events associated with either adalimumab or etanercept treatment versus placebo during
the double blind phases of either DE038 or Lovell et al. (2000).
The PBAC noted that comparative data on safety are minimal and this limits the conclusions
which may be drawn from this evidence. However, as the adverse events are qualitatively
similar to those in adults the PBAC was reassured of the relative safety of adalimumab
and etanercept in children.
The submission provided additional data on potential safety concerns beyond those
identified in the clinical trials. The submission stated that the product information
submitted to the TGA for approval contains the most up to date adverse event information.
The TGA Clinical Evaluator’s Report indicated that the safety of adalimumab in juvenile
idiopathic arthritis is very similar to that which has emerged from the experience
of adalimumab used in the treatment of rheumatoid arthritis.
9. Clinical Claim
The submission described adalimumab as non-inferior in terms of
comparative effectiveness and non-inferior in terms of comparative
safety over etanercept.
The PBAC concluded that, despite the issues of uncertainty, it was
reasonable to accept the submission’s claim of
non-inferiority of adalimumab compared with etanercept in regard to
effectiveness and safety.
10. Economic Analysis
The submission presented a cost minimisation analysis. The
equi-effective doses were estimated using the fixed dose regimen
specified in the Product Information and used in the open label
extension (OLE) phase of trial DE038. They are, adalimumab: 15 kg
to less than 30 kg: 20 mg and equal to or greater than 30 kg: 40 mg
sub-cutaneously once every second week compared with etanercept:
0.4 mg/kg up to 25 mg sub-cutaneously twice weekly. The total cost
for 4 weeks of treatment with adalimumab was the same as
etanercept, $1,630.00.
11. Estimated PBS Usage and Financial Implications
The likely number of patients/year (accounting for market share as necessary) was estimated by the submission to be less than 10,000 patients in Year 5. The PBAC noted the submission’s estimate was uncertain due to:
- Potentially underestimated growth assumption
- Omission of patients aged greater than 18 years in the potential patient estimates, who may receive continued treatment for JIA on PBS.
- Uncertainties with the proportions of patients who will continue treatment with adalimumab after failing treatment with etanercept. This depends on whether a treatment cycle is to be applied to the PBS listing of biologicals for JIA.
The financial cost/year to the PBS was estimated by the submission
to be less than $10 million in Year 5. The PBAC noted that the
submission’s estimate was uncertain due to the uncertain
estimates of patients to receive treatment with adalimumab each
year.
12. Recommendation and Reasons
The PBAC recommended listing as a pharmaceutical benefit on a cost
minimisation basis compared with etanercept under section 100
(Highly Specialised Drugs Program) Public and Private Hospital
Authority Required for severe active polyarticular course juvenile
idiopathic arthritis. The equi-effective doses estimated using the
fixed dose regimen specified in the PI and used in the OLE phase of
trial DE038, are adalimumab: 15 kg to less than 30 kg: 20 mg and
equal to or greater than 30 kg: 40 mg sub-cutaneously once every
second week compared with etanercept: 0.4 mg/kg up to 25 mg
sub-cutaneously twice weekly. The PBAC also agreed to listing for
patients greater than 18 years with an authority required
restriction.
The PBAC noted that the efficacy of adalimumab is superior when
used in combination with methotrexate and clinicians would
therefore use it in this combination whenever possible. The
Committee therefore did not consider that the requested restriction
should be amended to explicitly require adalimumab to be used in
combination with methotrexate in patients who are able to tolerate
methotrexate. The Committee agreed that the restriction should
allow interchangeability with etanercept and allow a total of three
attempts (two of one of either adalimumab or etanercept and one of
the other).
The PBAC agreed that the patients enrolled in the adalimumab trial
are not wholly representative of those for whom listing is sought
as the submission estimates that less than 50 % of patients from
Trial DE038 would qualify for adalimumab treatment on PBS. However,
it was also noted that the design of the trials for the etanercept
submission considered in December 2002 were similar and would have
had a similar issue with applicability of the trial
population.
As acknowledged by the submission, there were differences in
baseline characteristics, concomitant background medication and
different time periods of comparisons, although the withdrawal
design of the trials was similar. The PBAC noted that the point
estimate favours etanercept in the indirect comparison results at
16 weeks, but that these results are likely to be biased against
adalimumab because etanercept is shorter acting.
The PBAC noted that comparative data on safety are minimal and this
limits the conclusions which may be drawn from this evidence.
However, as the adverse events are qualitatively similar to those
in adults the PBAC, was reassured of the relative safety of
adalimumab and etanercept in children.
The PBAC concluded that, despite the issues of uncertainty, it was
reasonable to accept the submission’s claim of
non-inferiority of adalimumab compared with etanercept in regard to
effectiveness and safety.
Recommendation:
ADALIMUMAB, injection, 20 mg in 0.4 mL, 40 mg in 0.8 mL, pre-filled
syringe, pre-filled pen
Extend the current restriction to include:
Section 100 listing
(Highly Specialised Drug)
Public and Private hospital authority required
To be finalised
Pack size: 2
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
Abbott Australasia Pty Ltd is pleased that adalimumab will be reimbursed for patients with polyarticular juvenile idiopathic arthritis.
