Adalimumab, injection, 40 mg in 0.8 mL pre-filled syringe, 40 mg in 0.8 mL pre-filled pen, Humira®, March 2009
Public summary document for Adalimumab, injection, 40 mg in 0.8 mL pre-filled syringe, 40 mg in 0.8 mL pre-filled pen, Humira®, March 2009
Page last updated: 03 July 2009
Public Summary Document
Product: Adalimumab, injection, 40 mg in 0.8 mL
pre-filled syringe, 40 mg in 0.8 mL pre-filled pen,
Humira®
Sponsor: Abbott Australasia Pty Ltd
Date of PBAC Consideration: March 2009
1. Purpose of Application
The submission sought an extension to the current Authority
required listing to include treatment of severe chronic plaque
psoriasis.
2. Background
At the July 2008 meeting, the PBAC rejected the submission for
adalimumab for the treatment of severe chronic plaque psoriasis on
the grounds of uncertain clinical effectiveness and the resulting
uncertain cost-effectiveness of adalimumab when compared with
efalizumab.
3. Registration Status
Adalimumab was TGA registered on 17 April 2008 for the treatment of
moderate to severe chronic plaque psoriasis in adult patients who
are candidates for systemic therapy or phototherapy.
Adalimumab is also TGA registered for:
- Rheumatoid Arthritis
- Psoriatic Arthritis
- Ankylosing Spondylitis
- Crohn Disease
4. Listing Requested and PBAC’s View
The requested listing was similar to the other biological disease
modifying antirheumatic drugs (bDMARDs) for the treatment of severe
chronic plaque psoriasis, with initial therapy consisting of 16
weeks of treatment.
5. Clinical Place for the Proposed Therapy
Adalimumab will provide clinicians with an alternative bDMARD
therapy for patients suffering with severe chronic plaque psoriasis
whose condition is refractory to other systemic treatments or
phototherapy.
6. Comparator
The submission nominated efalizumab as the main comparator and
infliximab as a secondary comparator. This is as previously advised
by the PBAC (See Public Summary Document July 2008).
The PBAC noted the withdrawal of efalizumab from the Australian
market due to new safety concerns rather than doubts about the
effectiveness of the drug. Given that the submitted
cost-effectiveness analysis could not have taken these new safety
concerns into account, the PBAC agreed that it still provided a
suitable frame of reference against the other biological medicines
which remain PBS-listed consistent with the restriction requested
for adalimumab.
Of the remaining bDMARDS PBS-listed for chronic plaque psoriasis,
the PBAC considered that etanercept would be the more appropriate
main comparator due to the similar manner of administration.
For PBAC’s view, see Recommendation and
Reasons.
7. Clinical Trials
One additional adalimumab trial supplemented the evidence presented
in the July 2008 submission.
The basis of the submission was an indirect comparison of initial
PASI 75 response employing meta-analyses of four randomised
double-blind adalimumab trials and five randomised double-blind
efalizumab (main comparator) trials; the four adalimumab trials
versus four randomised double-blind infliximab (secondary
comparator) trials; with placebo as the common reference for all
comparisons. Long-term response was assessed using an unadjusted
indirect comparison of active treatment arms of one adalimumab
trial and one infliximab trial. No comparison of long-term response
of adalimumab and efalizumab was provided.
The additional trial presented, M04-688, was a 24 week randomised
trial comparing adalimumab to placebo at doses of 40 mg week 0, 40
mg week 2, then 40mg every fortnight; 80 mg week 0, 40 mg week 1,
then 40mg every fortnight; and 80 mg week 0, 80 mg every
fortnight.
8. Results of Trials
The key results for initial PASI 75 response, comparing adalimumab versus efalizumab
and adalimumab versus infliximab, showed that the proportion of patients with an initial
PASI 75 response was statistically significantly greater with adalimumab compared
to efalizumab (OR=3.05; 95% CI: 1.77, 5.26; p=0.0001) and statistically significantly
lower with adalimumab compared to infliximab (OR=0.26; 95% CI: 0.12, 0.55; p=0.0005).
The submission stated that a comparison of longer-term efficacy between adalimumab
and efalizumab could not be made due to lack of efalizumab data and as such only provided
a comparison of adalimumab and infliximab for longer-term response. The PBAC noted
that there is some long-term data available, in a format similar to that used by the
submission for its comparison of adalimumab and infliximab long-term response. However,
this trial data did not include a placebo-controlled arm beyond initial 12 week treatment,
and therefore an indirect comparison of adalimumab and efalizumab for long-term response
was not possible.
The submission based its assessment of long-term response on an unadjusted indirect
comparison of one adalimumab trial (REVEAL) and one infliximab trial (EXPRESS). The
two trials differed significantly in design, a key difference being that in the adalimumab
trial only patients who maintained a PASI 75 response are re-randomised at week 33,
whereas in the infliximab trial all placebo-treated patients are crossed-over to infliximab.
The unadjusted indirect comparison presented in the submission included only those
patients who were PASI 75 responders at week 12. However, the complex cross-over design
of the trials results in a lack of a placebo-controlled arm in both the adalimumab
and infliximab trials, such that the submission compared two single arms from each
trial.
In the REVEAL trial, the submission determined that there were 423 responders at week
52 who had initial response at week 16 giving a response rate of 72.93% (423/580).
In the EXPRESS trial, patients randomised to placebo were crossed over to infliximab
at week 24 and as such, there is no placebo-controlled data available beyond that
point. Long-term data is available for patients who achieved PASI 75 at week 10 and
maintained that response to week 50. In the EXPRESS trial, 242 of 310 patients were
responders at week 10. Of the 242 initial responders, 153 were responders at week
50. There were 17 patients who were not assessed at week 50 and the submission assumed
these patients were non-responders, resulting in a response rate 63.22% (153/242).
The responders from REVEAL and EXPRESS were then compared to provide an assessment
of long-term response. The table below provides the results of the unadjusted indirect
comparison presented.
Unadjusted indirect comparison of adalimumab and infliximab – initial PASI 75 response
maintained at week 52
| Treatment | Initial PASI 75 responders with response at week 52 | OR (95% CI) | RR (95% CI) | RD (95% CI) |
| Adalimumab | 423/580 (72.93%) a | 1.57 (1.14, 2.16) | 1.15 (1.04, 1.29) | 0.10 (0.03, 0.17) |
| Infliximab | 153/242 (63.22%) |
a chi square test p=0.0056
The PBAC noted that while a greater proportion of adalimumab patients maintained response
at week 52, the design of the trials and the methodology used to generate this outcome
leads to some uncertainty. The submission’s unadjusted indirect comparison, in which
arms of different trials are compared and randomisation is lost, is an approach recommended
against in the literature (Gartlehner and Moore 2008) and considered no more valid
than a comparison based on observational studies (Sutton et al., 2008). In addition,
the response rate for the adalimumab arm (72.93%) includes patients who were re-randomised
to placebo (almost half the total group), and it was assumed they would have the same
response rate as those re-randomised to adalimumab.
The submission also presented an indirect comparison of week 24 and week 52 response
comparing adalimumab and infliximab. However, as noted by the submission, these analyses
did not control or allow for the PBS stopping rule (ie patients who do not respond
to initial treatment are included) and as such were not directly applicable to the
conditions under which adalimumab will be used under PBS listing.
The submission provided indirect comparisons of any adverse events, serious adverse
events and discontinuations due to adverse events, with results indicating statistically
significant advantages for adalimumab compared to efalizumab and compared to infliximab.
The submission did not provide comparisons of treatment-related adverse events, even
though data appropriate for analysis was available, nor did the submission provide
an assessment of long-term safety.
The submission presented additional data addressing rebound following efalizumab treatment
and the incidence of positive antibodies to infliximab that was not presented in the
July 2008 submission. The submission calculated a probability of rebound of 18% in
non-responders to efalizumab. However the study from which this data was sourced reports
that rebound also occurred in 11% of patients treated with placebo. Rebound was defined
as PASI 125% of baseline or new, generalised pustular, erythrodermic or more inflammatory
psoriasis occurring within 3 months of discontinuation of treatment. Rebound criteria
may be fulfilled by variations in severity of psoriasis as part of natural history
of disease and may be unrelated to treatment withdrawal.
For PBAC’s comments, see Recommendation and Reasons.
9. Clinical Claim
The submission made the following claims regarding the comparison
with efalizumab:
- adalimumab is superior in terms of comparative effectiveness for
initial treatment response and superior in terms of comparative
safety during the initial treatment period;
- although long-term data for efalizumab was not available, since
the initial treatment response with adalimumab was well-maintained,
the superiority of adalimumab over efalizumab can also be
expected to be maintained.
The PBAC agreed that, based on the adjusted indirect comparison
provided in the submission, adalimumab is more effective than
efalizumab following the initial treatment period. However, as no
comparisons of long-term response versus efalizumab were made by
the submission, there was no basis to assume that the superiority
over efalizumab would be maintained.
In regard to comparative safety, the PBAC considered that it may be
more appropriate to consider that adalimumab and efalizumab are
similar in terms of safety.
The submission made the following claims in regard to the
comparison with infliximab:
- adalimumab is inferior to infliximab in terms of comparative
effectiveness for initial treatment response and superior in terms
of comparative safety during the initial treatment;
- adalimumab is superior in terms of maintaining response over one
year of treatment and is non-inferior to infliximab after one year
of treatment according to PBS listing criteria.
The PBAC agreed that, based on the adjusted indirect comparison
provided in the submission, adalimumab is less effective than
infliximab following the initial treatment period. However, the
PBAC did not accept the claim that adalimumab is more effective
than infliximab in terms of maintaining long-term response and
initial safety due to uncertainty regarding the use of a comparison
of the results of single-arm studies of adalimumab and
infliximab.
10. Economic Analysis
The submission presented a cost-effectiveness analysis comparing
adalimumab and efalizumab, as well as a cost-minimisation analysis
comparing adalimumab and infliximab.
For the cost-effectiveness analysis, a stepped economic evaluation
was used, culminating in a cost-utility analysis comparing
adalimumab and efalizumab. The type of model used was a Markov
cohort model with ten health states running for a duration of five
years.
The submission also presented a cost-minimisation analysis
comparing adalimumab and the secondary comparator infliximab.
For PBAC’s view, see Recommendation and
Reasons.
11. Estimated PBS Usage and Financial Implications
The submission estimated the likely number of initiating and
continuing courses/year to be less than 10,000 in year 5.
The submission estimated financial savings/year to the PBS
(excluding co-payments) to be less than $10 million in year 5. This
differed considerably from the July 2008 submission.
12. Recommendation and Reasons
The PBAC recommended listing adalimumab on the PBS for the
treatment of severe chronic plaque psoriasis on a cost-minimisation
basis with efalizumab or etanercept at TGA-recommended steady state
continuous doses (ie adalimumab 40 mg fortnightly and efalizumab 1
mg weekly and etanercept 50 mg weekly are equi-effective). The PBAC
agreed that the listing of adalimumab on the PBS for this condition
would offer an alternative therapy for subcutaneous use.
The PBAC noted that there were some difficulties with interpreting
the cost-effectiveness analysis comparing adalimumab with
efalizumab due to withdrawal of efalizumab from the Australian
market. The PBAC acknowledged that efalizumab was the comparator
requested in the July 2008 Minutes. The withdrawal of efalizumab
had been due to new safety concerns rather than doubts about the
effectiveness of the drug. Given that the submitted
cost-effectiveness analysis could not have taken these new safety
concerns into account, the PBAC agreed that it provided a suitable
frame of reference against the other biological medicines which
remain PBS-listed consistent with the restriction requested for
adalimumab.
The PBAC noted that, without efalizumab listed on the PBS, there
would only be two such drugs listed: infliximab, which is given by
intravenous administration and etanercept, given subcutaneously. Of
these, the PBAC considered that etanercept would be the more
appropriate main comparator due to the similar manner of
administration.
The PBAC agreed that, based on the adjusted indirect comparison
provided in the submission, adalimumab is more effective than
efalizumab following the initial treatment period. However, as no
comparisons of long-term response versus efalizumab were made by
the re-submission, there was no basis to assume that the
superiority over efalizumab would be maintained. On the basis of
single-arm studies of the various options which have been assessed
for the requested restriction, the maintenance of response appears
to vary, but there are no randomised trial results from which a
direct or indirect comparison can be made. The PBAC therefore
concluded that the re-submission had not convincingly demonstrated
that adalimumab is more effective than efalizumab overall.
The PBAC therefore did not accept the claim of cost-effectiveness
over efalizumab as a basis for recommending the listing of
adalimumab as requested. It concluded that a cost-minimisation
basis would be more appropriate. In this regard, the parallel PBAC
recommendation for continuous etanercept on a cost-minimisation
basis with efalizumab is relevant because etanercept is not being
removed from the Australian market.
The PBAC also rejected the cost-minimisation analysis comparing
adalimumab with infliximab, the secondary and less relevant
comparator, due to clinical uncertainty.
The PBAC agreed that, based on the adjusted indirect comparison
provided in the submission, adalimumab is less effective than
infliximab following the initial treatment period. However, the
PBAC did not accept the claim that adalimumab is more effective
than infliximab in terms of maintaining long-term response and
initial safety due to uncertainty regarding the use of a comparison
of the results of single-arm studies of adalimumab and infliximab.
The PBAC considered that there were insufficient data on long-term
comparative effectiveness and noted that the design of the
single-arm follow-ups of the two trials providing such longer-term
data differ widely. For example, a key difference is that, in the
follow-up study from the adalimumab trial (REVEAL), only patients
who maintained a PASI 75 response are re-randomised at week 33,
whereas in follow-up study from the infliximab trial (EXPRESS), all
placebo-treated patients are crossed over to infliximab).
In regard to comparative safety, the re-submission did not provide
analyses of drug-related adverse events. In addition, there were no
differences in the proportion of patients with serious adverse
events or those who discontinued treatment due to an adverse event.
Thus, the PBAC considered that it may be more appropriate to
consider that adalimumab and infliximab are similar in terms of
safety.
The PBAC considered that the therapeutic relativity of 1.6983
between adalimumab and infliximab calculated in the
cost-minimisation analysis may not be accurate, given that the
greater number of infliximab vials used was due largely to the use
of a patient sample with greater weight, and noted that these data
were also used to determine the proportion continuing
treatment.
The PBAC considered that the financial implications estimates
presented by the re-submission did not reflect the actual impact of
the listing of adalimumab, given that the re-submission’s
estimates of effectiveness influenced the calculation of estimated
financial implications but are not strongly supported. In addition,
the re-submission did not address the possibility that PBS listing
for adalimumab may increase the market size.
Recommendation
The PBS listing restriction can be found in the Schedule of
Pharmaceutical Benefits at www.pbs.gov.au
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 is pleased that patients will benefit from this
positive result.
