PBAC Review of bDMARDs for the treatment of severe active rheumatoid athritis
Public Summary Document for bDMARDs, for the treatment of severe active rheumatoid athritis.
Page last updated: 19 February 2010
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Public Summary Document
Products and Sponsors:
abatacept (Orencia®), Bristol-Myers Squibb Pharmaceuticals Pty Ltd; anakinra (Kineret®), PharmaLink Pty Ltd; adalimumab (Humira®), Abbott Australasia Pty Ltd; etanercept (Enbrel®), Wyeth Australia Pty Limited; infliximab (Remicade®), Schering-Plough Pty Ltd; and rituximab (Mabthera®), Roche Products Pty Ltd,
Date of PBAC Consideration:
December 2009
1. Purpose
To review the clinical and cost-effectiveness data of the
biological disease-modifying antirheumatic drugs (bDMARDs):
abacept, anakinra, adalimumab, etanercept, infliximab and
rituximab, currently subsidised via the Pharmaceutical Benefits
Scheme (PBS) for the treatment of severe, active rheumatoid
arthritis.
2. Background
There are six biological disease modifying anti-rheumatic drugs
(bDMARDs) subsidised via the PBS for the treatment of rheumatoid
arthritis. These are adalimumab, etanercept, infliximab, rituximab,
abatacept and anakinra. These bDMARDs have different mechanisms of
action: three tumour necrosis factor (TNFα) inhibitors
(adalimumab, etanercept, infliximab), a CD20-specific monoclonal
antibody (rituximab), a T-cell co-stimulation modulator (abatacept)
and an interleukin-1 (IL-1) inhibitor (anakinra).
Etanercept was the first bDMARD to receive a positive
recommendation from the Pharmaceutical Benefits Advisory Committee
(PBAC) in December 2002. Adalimumab and infliximab were listed on a
cost-minimisation basis compared to etanercept, while abatacept was
listed on a cost-minimisation basis compared to infliximab.
Rituximab was listed on a cost-minimisation basis compared to
etanercept and adalimumab, with the proviso that to be eligible for
treatment with rituximab, patients must have already failed to
demonstrate a response to at least one course of treatment with a
PBS-subsidised TNF-α inhibitor (adalimumab, etanercept,
infliximab). Anakinra was listed on the basis of acceptable
cost-effectiveness compared with a subsequent TNF-α inhibitor
in patients who are unresponsive to, or intolerant of one or more
prior TNF-α inhibitors, or in whom one or more prior
TNFα-inhibitors are contra-indicated.
Access to PBS subsidised treatment with one of the bDMARDs listed
on the PBS is limited to patients who meet certain eligibility
criteria including having severe, active rheumatoid arthritis and
failing to respond to non-biological disease modifying
anti-rheumatic drugs (DMARD) used to treat rheumatoid arthritis. If
a patient fails to achieve a preset response to a bDMARD, they
cannot continue with PBS subsidised treatment with that bDMARD. If
a patient fails to respond to bDMARD treatment three times they
must have a minimum break of five years from biologic therapy
before they are allowed to receive further subsidised
bDMARDs.
The data considered by PBAC when it recommended the bDMARDs be
subsidised through the PBS included estimates of the number of
patients who would initiate and continue treatment in clinical
practice. These estimates were based on factors including the
incidence and prevalence of severe active rheumatoid arthritis and
the percentage of patients who continued treatment in the clinical
trials conducted with each agent.
In December 2008, the Department of Health and Ageing asked PBAC
for advice on the higher than estimated usage of the
TNFα-inhibitors in rheumatoid arthritis. At that time the
Committee considered that there were several factors which could
account for the higher continuation rates observed in Australian
clinical practice compared to those from clinical trials,
including:
- higher doses of methotrexate and combination therapy are used in clinical practice which may lead to better patient responses to bDMARD therapy;
- the efficacy endpoint for the restrictions is a “hybrid” of the endpoints used in clinical trials which may be a factor in the higher continuation rates seen in practice;
- it is possible for prescribers to assess a patient’s response more favourably to avoid a treatment failure being recorded; and
- better management of nuisance adverse effects such as injection site reactions, abnormalities of liver function tests and haematology.
The PBAC also considered
that the impact on the clinical and cost-effectiveness of bDMARD
treatment of more Australian patients remaining on treatment and
for longer periods than was observed in clinical trials was unknown
and requested that a review of cost-effectiveness of the bDMARDs be
conducted.
3. Summary of Review and Findings
Results of the randomised controlled trials:
With the exception of one trial comparing abatacept and infliximab (Schiff et al.
2008) there are no head-to-head trials comparing any of the bDMARDs. Therefore, the
systematic review of efficacy and of adverse events considered by PBAC involved meta-analyses
of indirect comparisons using Mixed Treatment Comparisons (MTC), based on the methods
used by Nixon et al. (2007) [Nixon RM, Bansback N, Brennan A. Using mixed treatment
comparisons and meta-regression to perform indirect comparisons to estimate the efficacy
of biologic treatments in rheumatoid arthritis. Stat Med 2007;26(6):1237-54.]
The following table lists the key, randomised trials considered in the comparison
of the bDMARDs. All trials were included in the Mixed Treatment Comparison, with the
exception of Klareskog et al. (2004) which had patients who did not fail DMARD treatment.
Publication details of the trials included in the efficacy Mixed Treatment Comparison
| Trial | Publications |
| Etanercept | |
| Moreland et al (1999) | Moreland LW, Schiff MH, Baumgartner SW, et al . Etanercept therapy in rheumatoid arthritis. A randomized, controlled trial. Ann Intern Med 1999;130(6):478-86. |
| Weinblatt et al (1999) | Weinblatt ME, Kremer JM, Bankhurst AD, et al . A trial of etanercept, a recombinant tumor necrosis factor receptor:Fc fusion protein, in patients with rheumatoid arthritis receiving methotrexate. N Engl J Med 1999;340(4):253-9. |
| Klareskog et al (2004) (TEMPO) |
Klareskog L, van der Heijde D, de Jager JP, et al . Therapeutic effect of the combination of etanercept and methotrexate compared with each treatment alone in patients with rheumatoid arthritis: double-blind randomised controlled trial. Lancet 2004;363(9410):675-81 van der Heijde D, Klareskog L, Singh A, et al . Patient reported outcomes in a trial of combination therapy with etanercept and methotrexate for rheumatoid arthritis: the TEMPO trial. Ann Rheum Dis 2006;65(3):328-34. van der Heijde D, Klareskog L, Rodriguez-Valverde V, et al . Comparison of etanercept and methotrexate, alone and combined, in the treatment of rheumatoid arthritis: two-year clinical and radiographic results from the TEMPO study, a double-blind, randomized trial. Arthritis Rheum 2006;54(4):1063-74. |
| Combe et al (2006) (Study 309) | Combe B, Codreanu C, Fiocco U, et al . Etanercept and sulfasalazine, alone and combined, in patients with active rheumatoid arthritis despite receiving sulfasalazine: a double-blind comparison. Ann Rheum Dis 2006;65(10):1357-62. |
| Adalimumab | |
| Furst et al (2003) (STAR) | Furst DE, Schiff MH, Fleischmann RM, et al . Adalimumab, a fully human anti tumor necrosis factor-alpha monoclonal antibody, and concomitant standard antirheumatic therapy for the treatment of rheumatoid arthritis: results of STAR (Safety Trial of Adalimumab in Rheumatoid Arthritis). J Rheumatol 2003;30(12):2563-71. |
| Weinblatt et a l (2003) (ARMADA) | Weinblatt ME, Keystone EC, Furst DE, et al . Adalimumab, a fully human anti-tumor necrosis factor alpha monoclonal antibody, for the treatment of rheumatoid arthritis in patients taking concomitant methotrexate: the ARMADA trial. Arthritis Rheum 2003;48(1):35-45. |
| Keystone et al (2004) (DE019) |
Keystone EC, Kavanaugh AF, Sharp JT, et al. 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: a randomized, placebo-controlled, 52-week trial. Arthritis Rheum 2004;50(5):1400-11. Jamal S, Patra K, Keystone EC. Adalimumab response in patients with early versus established rheumatoid arthritis: DE019 randomized controlled trial subanalysis. Clin Rheumatol 2009;28(4):413-9. |
| van de Putte et al (2004) | van de Putte LB, Atkins C, Malaise M, et al . 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):508-16. |
| Infliximab | |
| Maini et al (1999) (ATTRACT) |
Maini R, St Clair EW, Breedveld F, et al . Infliximab (chimeric anti-tumour necrosis factor alpha monoclonal antibody) versus placebo in rheumatoid arthritis patients receiving concomitant methotrexate: a randomised phase III trial. ATTRACT Study Group. Lancet 1999;354(9194):1932-9. Lipsky PE, van der Heijde DM, St Clair EW, et al . Infliximab and methotrexate in the treatment of rheumatoid arthritis. Anti-Tumor Necrosis Factor Trial in Rheumatoid Arthritis with Concomitant Therapy Study Group. N Engl J Med 2000;343(22):1594-602. |
| Westhovens et al (2006) (START) | Westhovens R, Yocum D, Han J, et al . The safety of infliximab, combined with background treatments, among patients with rheumatoid arthritis and various comorbidities: a large, randomized, placebo-controlled trial. Arthritis Rheum 2006;54(4):1075-86. |
| Abatacept | |
| Genovese et al (2005) (ATTAIN) | Genovese MC, Becker JC, Schiff M, et al . Abatacept for rheumatoid arthritis refractory to tumor necrosis factor alpha inhibition. N Engl J Med 2005;353(11):1114-23. |
| Kremer et a l (2006) (AIM) |
Kremer JM, Genant HK, Moreland LW, et al . Effects of abatacept in patients with methotrexate-resistant active rheumatoid arthritis: a randomized trial. Ann Intern Med 2006;144(12):865-76. Russell AS, Wallenstein GV, Li T, et al . Abatacept improves both the physical and mental health of patients with rheumatoid arthritis who have inadequate response to methotrexate treatment. Ann Rheum Dis 2007;66(2):189-94. |
| Anakinra | |
| Cohen et al (2004) | Cohen SB, Moreland LW, Cush JJ et al . A multicentre, double blind, randomised, placebo controlled trial of anakinra (Kineret), a recombinant interleukin 1 receptor antagonist, in patients with rheumatoid arthritis treated with background methotrexate. Ann Rheum Dis 2004;63:1062-68. |
| Infliximab + abatacept | |
| Schiff et al (2008) (ATTEST) | Schiff M, Keiserman M, Codding C, et al . Efficacy and safety of abatacept or infliximab vs placebo in ATTEST: a phase III, multi-centre, randomised, double-blind, placebo-controlled study in patients with rheumatoid arthritis and an inadequate response to methotrexate. Ann Rheum Dis 2008;67(8):1096-103. |
| Rituximab | |
| Edwards et al (2004) |
Edwards JC, Szczepanski L, Szechinski J, et al . Efficacy of B-cell-targeted therapy with rituximab in patients with rheumatoid arthritis. N Engl J Med 2004;350(25):2572-81. Strand V, Balbir-Gurman A, Pavelka K, et al . Sustained benefit in rheumatoid arthritis following one course of rituximab: improvements in physical function over 2 years. Rheumatology (Oxford) 2006;45(12):1505-13. |
| Cohen et al (2006) (REFLEX) | Cohen SB, Emery P, Greenwald MW, et al . Rituximab for rheumatoid arthritis refractory to anti-tumor necrosis factor therapy: Results of a multicenter, randomized, double-blind, placebo-controlled, phase III trial evaluating primary efficacy and safety at twenty-four weeks. Arthritis Rheum 2006;54(9):2793-806. Keystone E, Burmester GR, Furie R, et al . Improvement in patient-reported outcomes in a rituximab trial in patients with severe rheumatoid arthritis refractory to anti-tumor necrosis factor therapy. Arthritis Rheum 2008;59(6):785-93. |
| Emery et al (2006) (DANCER) | Emery P, Fleischmann R, Filipowicz-Sosnowska A, et al . The efficacy and safety of rituximab in patients with active rheumatoid arthritis despite methotrexate treatment: results of a phase IIB randomized, double-blind, placebo-controlled, dose-ranging trial. Arthritis Rheum 2006;54(5):1390-400. |
The odds ratios (OR) for achieving a response compared with the control groups from
the Mixed Treatment Comparison are presented in the table below.
Odds ratios from the mixed treatment comparison
| Drug | ACR20 OR (95% CI) | ACR50 OR (95% CI) | LDAS OR (95% CI) | EULAR good/moderate OR (95% CI) |
| Abatacept | 4.22 (2.54, 6.63) | 5.58 (3.39, 9.16) | 4.41 (1.25, 16.66) | NA |
| Adalimumab | 3.02 (2.13, 5.13) | 3.66 (2.46, 5.60) | NA | 1.01 (0.00, 5.3x10 6 ) |
| Anakinra | 2.05 (1.00, 4.31) | 2.11 (1.05, 4.44) | NA | NA |
| Etanercept a | 10.03* (5.23, 18.15) | 15.88* (7.42, 36.15) | 1.56 (0.13, 23.84) | NA |
| Infliximab | 3.29 (1.80, 5.78) | 4.90 (2.67, 9.25) | 9.61 (0.28, 382.0) | 10.94 (0.00, 4410.0) |
| Rituximab | 4.22 (2.47, 7.30) | 4.57 (2.67, 8.33) | 3.26 (0.11, 88.14) | 4.84 (1.35, 17.23) |
a Excluding Klareskog et al. (2004).
* the PBAC considered that there was uncertainty with the outcome of the Mixed Treatment
Comparison with regard to etanercept being superior to adalimumab and infliximab
ACR = American College of Rheumatology; LDAS = low disease activity score, defined
as a DAS28 of <3.2; EULAR = European League Against Rheumatism response; NA=not available
Bolded results are statistically significant
All of the bDMARDs demonstrated an advantage compared to the control arm for both
the ACR20 and ACR50 response.
Although between-drug comparisons revealed a statistically significant advantage for
etanercept versus all other drugs for ACR50, the PBAC agreed that there was uncertainty
with the outcome of the Mixed Treatment Comparison indicating that etanercept is superior
to adalimumab and infliximab. Other published analyses suggest that there are no differences
in efficacy between the anti-TNFs. The superiority of etanercept shown in the Mixed
Treatment Comparison could be attributed to the selection of data used, in particular
the use of only trial arms with PBS-listed drug doses. Further possible reasons are
the differences in covariates included in analyses. In the Mixed Treatment Comparison
approach, treatments are compared at the same value of the study-level covariates.
Other analyses may have ignored potentially significant study-level covariates which
may partly explain the estimated differences in efficacy between the bDMARDs.
The PBAC noted that the Mixed Treatment Comparison showed anakinra to be inferior
to the other bDMARDs. The PBAC further noted that the UK National Institute of Clinical
Excellence (NICE) treatment guidelines do not recommend anakinra for the treatment
of rheumatoid arthritis, except in the context of a controlled, long-term clinical
study.
Comparative toxicity:
Overall, there was no statistically significant difference between the bDMARDs for
the occurrence of serious adverse events, withdrawals due to serious adverse events,
serious infections and malignancies. PBAC considered that although it appears that
the newer agents, rituximab and abatacept, may have better safety profiles than the
TNF inhibitors, long term data are lacking.
4. Economic Analysis
Model and assumptions
The Committee considered the results from a deterministic semi-Markov model developed
to model five different treatment sequences for the three anti-TNF drugs (etanercept,
adalimumab and infliximab), rituximab and abatacept. Each treatment sequence used
in the base case and scenario analyses included three treatments as allowed under
the current PBS bDMARD subsidy arrangements that allow patients to trial three treatments
in sequence and if they fail all three treatments, requires a five year break from
bDMARD therapy.
Anakinra was excluded from the modelled economic analysis because the Mixed Treatment
Comparisons revealed that anakinra was inferior to the other bDMARDs and because it
has relatively small usage under the PBS.
For the base-case analysis, the continuation rates (i.e. response rates) for the bDMARDs
were derived from Medicare Australia data from March 2003 to 31 May 2009. The PBAC
considered that it was appropriate to use Medicare data to inform the response rates
in the base-case economic model as this data is specific to the outcome criteria specified
in the PBS restrictions. Scenario analyses were undertaken using the trial-based outcomes.
The continuation rates for the initial period (the proportion of patients continuing
with the same bDMARD after the initial assessment) and the mean continuation rates
for subsequent periods which were used to model the base case are presented in the
following table.
Continuation (response) derived from Medicare data
|
bDMARD |
Initial period |
Subsequent periods |
|
Etanercept |
0.761 |
0.787 |
|
Infliximab |
0.722 |
0.746 |
|
Adalimumab |
0.707 |
0.726 |
|
Mean TNFs * |
0.733 |
0.725 |
|
All bDMARDs |
0.716 |
0.706 |
*this value is the mean for the three TNF alpha inhibitors and was used as an estimate
for the continuation rates for rituximab and abatacept in the economic evaluation
given the later listings of these agents.
It was noted that the continuation rates for rituximab and abatacept were lower than
for the other agents (initial period: 0.490 and 0.588; subsequent periods 0.393 and
0.437 respectively). The PBAC agreed that these lower continuation rates were likely
due to these being the last two drugs listed on the PBS but could also reflect that
these drugs may be used in more treatment resistant patients. The PBAC noted that
the use of the response rates for rituximab and abatacept based on Medicare data may
not reflect the true efficacy of these agents, hence the economic evaluation used
the mean continuation rates for the three TNF alpha inhibitors as an estimate for
the continuation rates for rituximab and abatacept.
The key assumptions used in the model considered by PBAC and the impact on the incremental
cost effectiveness ratio (ICER) that occurs if adjustments are made to this model
are listed below.
Key assumptions
|
Issue |
Comment |
Direction |
Approx magnitude |
||
|
Under-calculation of Medicare ‘Ongoing Continuations’ rates |
An identical time period (inception to May 2009) has been used when counting initial applications and continuing applications (or subsequent continuations following previous continuations). This underestimates the real continuation rate as a delay of approx 3 months following initiation to first continuation is required to enable all patients the time to have their initial therapy and have an assessment of eligibility for bDMARD continuation and have their subsequent application for continuing treatment made. If the continuation rates following initial treatment are re-estimated allowing for this lag time (ie using data only up to February 2009 to obtain a denominator of patient usage, but counting data up to May 2009 to estimate the numerator of continuing patients) the following continuation rates are obtained: |
Increase ICER |
>$2,000/ |
||
|
|
Medicare Rate in Review |
Revised Medicare |
|||
|
Etanercept |
0.761 |
0.800 |
|||
|
Infliximab |
0.722 |
0.751 |
|||
|
Adalimumab |
0.707 |
0.756 |
|||
|
Rituximab |
0.490 |
0.599 |
|||
|
Abatacept |
0.588 |
0.726 |
|||
|
TNFs |
0.733 |
0.777 |
|||
|
All bDMARDs |
0.716 |
0.767 |
|||
|
Under-calculation of Medicare ‘Initial Continuations’ rates |
As described above, the same methodological issue is present in calculations of the percentage of patients with an initial Medicare continuation. These values proxy for initial effectiveness in the base case. |
Increase ICER |
≈$2,000/ |
||
|
Quality of life in bDMARD responders is assumed to be maintained indefinitely while responding. |
Australian Rheumatology Association Database (ARAD) data (beyond 36 months) shows that Quality of Life (QoL) appears to diminish gradually over time, even in responders continuing on treatment. Given the progressive nature of the disease and the ability for partial response etc, this would seem more realistic than indefinitely maintained utility. |
Increase ICER |
≈$5,000/ |
||
|
Administration costs do not include hospital admissions or home nursing. |
Infusions of rituximab, infliximab and abatacept require day stay hospital admission costs and will attract higher administration costs than the MBS fee included in the model**. Some patients on etanercept or adalimumab need assistance with injecting, therefore some home nursing costs should be included. |
Increase ICER |
≈$25,000/ |
||
|
DMARD response of 15% in previously refractory patients. |
The base case estimate of 15% appears reasonable, but highly uncertain given its non-evidentiary
source. Alternatives were tested in sensitivity analyses. |
Decrease or |
- ≈$2,000 to + ≈$20,000/ |
||
|
Unreasonable assumption that surgery is utility neutral |
As an accurate estimate of utility benefit was not easily obtained, but benefits must be considered to exceed risks and should be of acceptable cost-effectiveness for surgery to proceed, excluding this completely may be more reasonable than including only costs. |
Increase ICER |
<$2,000/ |
||
|
Timeframe is long |
Likely changes in treatment methods etc over time increase likelihood of irrelevance of model over time, consideration to shorter timeframes would be reasonable. |
Increase ICER |
ICER increases as time horizon decreases. |
||
|
Long-term adverse events excluded |
No specific adverse event rates or costs available. |
Increase ICER |
Unknown |
||
|
Monitoring costs are incomplete |
The recommendations and usual clinical practice with respect to monitoring (eg blood tests [ESR,CRP,FBC,Cr,LFT etc] and screening, GP and specialist review visits) were revised. The full costs of screening for TB, HIV, hepatitis etc are still not included, favouring bDMARDs, but unlikely to be of consequence. |
ICER may remain slightly under-estimated |
Unlikely to have substantial impact on ICER. |
||
|
The bDMARD naive treatment effect in 2nd/3rd/4th treatments is maintained. |
This is tested in the sensitivity analyses with assumptions of decreased efficacy diminished by 10% and 25% for each additional bDMARD. The assumption of decreasing response is supported by literature and may be considered appropriate in the base case. |
Decrease ICER |
≈$2,000 to ≈$6,500/ |
||
|
Effect size of etanercept (MTC) |
The relatively large initial effect size of etanercept derived from the MTC may be an artefact associated with the duration of treatment selected for this Review. The Cochrane review found a similar result at 6 months which had disappeared by 12 months. |
Decrease ICER |
≈$10,000 to ≈$20,000/ |
||
** The Committee did not accept the argument presented at the meeting hearing that
the provision by an individual sponsor of an infusion service for one of the bDMARDs
negates the need to include any costs associated with the administration of these
agents. The PBAC considered that as a minimum, the cost claimed by medical practitioners
for the administration of an IV infusion would be the MBS fee.
In particular, the PBAC discussed the following issues raised by the Australian sponsors
of bDMARDs:
- that the model assumed that the bDMARD treatment effect in the second, third and fourth bDMARDs is maintained which was favourable to the bDMARDs. This assumption was tested in sensitivity analyses presented in the final report, with a 10% and 25% reduction in efficacy for each additional bDMARD resulting in only a minor reduction in the ICER from approximately $2,000 to $6,500 per QALY.
- The economic analysis assumed that 15% of patients in the usual care arm (non-biologic) of the model have a period of remission of rheumatoid arthritis without bDMARD treatment. The PBAC noted that the rates of response from the DMARD arms of the trials estimated by the Mixed Treatment Comparisons were: ACR20 = 26.1%; ACR50 = 8.6%; LDAS = 4.4%; and EULAR = 33.9% which gave a crude overall mean of 18.2% and a crude mean of 17.3% for the ACR measures. Based on the results of the Mixed Treatment Comparison, the PBAC considered that the assumption of 15% for the remission of rheumatoid arthritis was reasonable. The PBAC further noted that when tested in sensitivity analysis, reducing the remission rate to 5% gave a minor reduction in the ICER in the order of $2,000 per QALY.
- The model assumed that in the usual care arm and in non-responders to bDMARDs there would be disease progression and an associated decline in utility. The model therefore imposed a rate of diminishing utility of 2% per annum which was based on the midpoint of values obtained from the literature, as shown in the table below. This was accepted by the PBAC.
Estimating utility in non-responders to bDMARDs and patients receiving usual care
|
CUA study |
Based on |
HAQ progression |
Utility decline per annum* |
|
Brennan et al 2004 |
Functional grade III and IV |
0.13 per annum |
-0.03 |
|
Brennan et al 2007 |
Conventional DMARDs |
0.042 per annum |
-0.01 |
|
Chen et al 2006 |
Palliation |
0.06 per annum |
-0.01 |
|
Kielhorn et al 2008 |
Palliation |
0.065 per 6 mth cycle |
-0.03 |
|
Kobelt et al 2005 |
“Standard treatment” |
0.03 per annum |
-0.01 |
|
Lindgren et al 2009 |
Off treatment |
0.03 per annum |
-0.01 |
|
Spalding et al 2006 |
“Natural progression” |
0.155 per 5 years |
-0.01 |
|
Tanno et al 2006 |
Conventional DMARDs |
0.067 per 6 mths |
-0.02 |
|
Vera-Llonch et al 2008 |
Conventional DMARDs |
0.065 per annum |
-0.01 |
|
Wailoo et al 2008 |
After withdrawal from bDMARDs |
0.02 per annum |
0.00 |
*Utility estimated using AQoL = 0.85 - 0.23HAQ from Hawthorne et al, 2000
One sponsor questioned the multiplicative approach used in the model to apply the
2% decline in utility in non-responders and in patients receiving usual care, which
used a log function. The sponsor argued that the decrement should have been applied
as an absolute reduction in utility rather than a relative reduction each year (i.e.
a linear decay versus a multiplicative decay). The PBAC considered that a multiplicative
decline was more appropriate as this approach results in an eventual asymptote in
utility at a value greater than zero. The PBAC also noted that for a linear decay,
the entire quality of life benefit would be driven only by rheumatoid arthritis which
ignores other factors which influence QALY measures.
Of those patients who no longer remain on the initiated bDMARD, some switch to another
bDMARD and a minority cease bDMARDs in favour of DMARDs. The table below provides
the percentages of patients who switch to another bDMARD as a result of failure (i.e.
a lack of response) or an adverse event.
Percentage of patients discontinuing one bDMARD who switch to another bDMARD
|
TNFs |
Etanercept |
Adalimumab |
Infliximab |
Rituximab |
Abatacept |
ALL |
|
0.804 |
0.789 |
0.704 |
0.918 |
0.804 |
0.804 |
0.804 |
In the absence of specific Medicare data, this information was extracted from the
Australian Rheumatology Arthritis Database (ARAD). The figures for switching were
derived by analysing ARAD data over a 36 month period, dividing the total number of
patients discontinuing a given bDMARD by the total number of patients who switched
to another bDMARD. For example, over 36 months 299 ARAD participants discontinued
etanercept, and of these, 236 switched to another bDMARD (78.9%). The sample of patients
recorded in the ARAD had not switched from rituximab or abatacept due to the relatively
late entry to market of these drugs and hence the numbers of patients using these
drugs were small and the opportunities for switching from these drugs was limited.
Therefore, it was assumed in the economic modelling that the rate of switching from
these latter drugs would be the same as the mean rate of switching from the TNFα inhibitors.
Results of the economic analysis
The base case incremental cost effectiveness ratio (ICER) for a representative treatment
sequence of three bDMARDs with differing mechanisms of action exceeded $100,000. The
corresponding ICER for the treatment sequence etanercept-adalumimab-infliximab most
commonly observed in the analysed Medicare data also exceeded $100,000. These ICERs
are above the range normally considered by PBAC to represent acceptable cost-effectiveness.
According to the semi-Markov model that was used, there were considerable differences
in total costs, total quality adjusted life years (QALYs) and ICERs depending on the
drug sequence and response measure used.
For example, using the ACR20 (American College of Rheumatology 20) as the outcome
measure resulted in higher ICERs than in the base case. On the other hand, the ICER
with the ACR50 (American College of Rheumatology 50) used as the continuation criteria
was lower than the base-case. This is due to fewer responders to bDMARDs and therefore
lower costs. Nevertheless, there are also fewer QALYs gained when ACR50 is used.
The LDAS (low disease activity score, defined as a DAS28 of <3.2) was the most stringent
criteria – or at least had the lowest rate of responders. The total costs for treatment
with bDMARDs were lowest for this outcome measure and QALYs were also lower. The PBAC
agreed with its economics subcommittee that while the ICERs based on the LDAS are
lower than the other response measures, in practice this outcome could not be adopted
for the purpose of PBS restrictions.
The EULAR (European League Against Rheumatism) good/moderate response criteria resulted
in ICERs similar to the base-case using Medicare continuation rates.
The PBAC also noted the results of an analysis of single administration of each agent
based on different utility instruments (AQoL, SF-6D and EQ-5D) as presented in the
Late Papers to the meeting Agenda.
While the use of the EQ-5D resulted in lower ICERs compared to the AQoL which was
used in the base case analysis, the PBAC considered that the AQoL was a more appropriate
outcome in the current circumstances, because it provides more detail about the quality
of life compared to the EQ-5D. The EQ-5D has only five dimensions and three levels
in each dimension, therefore this outcome measure is sensitive to significant changes
in one domain and there is more potential for one dimension to overstate the effect
of clinical measures. The PBAC noted the variability in the baseline EQ-5D scores
which suggested that this measure was less sensitive than the AQoL. The PBAC further
noted that around a third of the health states in the EQ-5D have negative values which
leads to a tendency for a larger difference in utility values between health states
than with other instruments. Overall, the PBAC considered that the ICERs based on
the EQ-5D are more uncertain compared to those based on the AQoL due to the EQ-5D
being less sensitive and could not be accepted in preference to the AQoL derived ICERs.
However, the EQ-5D results could form the lower boundary of an acceptable ICER.
The PBAC considered that the five year break in therapy required under the PBS restrictions
after failure to respond to three bDMARDs was no longer clinically appropriate given
the existence of multiple drugs with different mechanisms of actions and recommended
that this requirement be removed from the restrictions. PBAC recalled it had settled
on this exclusion period during its early considerations of the bDMARDs when only
a limited number of these medicines were available. At that time, the five year period
was seen as a reasonable timeframe to allow sponsors to obtain new data about the
efficacy of one bDMARD following failure of another bDMARD.
The Committee considered that revising the restriction to allow patients to trial
up to five bDMARDs would be appropriate to enable patients to try more treatments
with different modes of action. The PBAC therefore examined the cost-effectiveness
of trialing five bDMARDs in sequence, with no further bDMARD therapy after the fifth
bDMARD treatment. When using AQoL utility values, this resulted in ICERs which exceeded
$100,000 and were higher than in the base case reported above. The ICERs based on
the EQ-5D results were lower than in the base case. Overall, the ICERs for this scenario
remained unacceptably high to the Committee.
The Committee noted that examining the cost-effectiveness of a sequence of therapy
in the management of a disease was not usual as part of its decision making and recommended
that a policy framework be developed to address this issue. The Committee then agreed
that the appropriate and consistent decision context for assessing the cost effectiveness
of bDMARDs is the incremental cost-effectiveness ratio of a single administration
of an agent. This is compatible with other medicine classes where different agents
are used sequentially e.g. cytotoxic agents.
The ICERs for single administration of each agent using AQoL utility values were similar
to those reported for the base case modelled economic evaluation. Using EQ-5D utility
values, the ICERs were lower than in the base case. The PBAC again considered these
ICERs unacceptably high and that a significant price reduction is required so that
the ICERs fall within a range representing acceptable cost-effectiveness when these
agents are used for the treatment of Rheumatoid Arthritis.
5. Recommendation and Reasons
The PBAC noted that there are a large number of patients with
rheumatoid arthritis and acknowledged that there is a high clinical
need for the bDMARDs. The Committee was satisfied with the process
followed in the conduct of the review.
The Committee accepted the structure of the economic modelling used
in the review and was satisfied with the rigour of the evidence
used to inform the models assumptions. The use of Medicare
Australia continuation rates in the base case economic model was
accepted. The Committee noted that the approach used in the
economic modelling did not disadvantage the bDMARDs as it assumes
that there is no loss of response when a patient tries another
bDMARD.
The PBAC agreed that, with the exception of anakinra, which appears
inferior, there were no differences between the other five bDMARDs
in terms of efficacy and safety.
The Committee considered that their decision context for cost
effectiveness would be single administration of an agent. This is
compatible with other medicine classes where different agents are
used sequentially e.g. many cytotoxic agents.
Based on its overall considerations of the review, the PBAC
recommended the following changes to the PBS subsidy arrangements
for the bDMARDs.
- The current eligibility criteria for the bDMARDs be revised to ensure that they are consistent with the latest evidence for best practice with regard to the initiation of non-biological medicines in patients with rheumatoid arthritis. This reconsideration of the initiation rules should involve interaction with clinical experts and sponsors.
- The five year exclusion period between bDMARD treatments (after failure of three treatments) can no longer be justified. In its place, PBAC recommended the development of a new PBS restriction which allows patients to try a maximum of five bDMARDs within a life-time.
- The current continuation rules be maintained.
- The PBAC is minded to recommend removal of anakinra from the PBS. The sponsor should be given the opportunity to provide input to the Committee on this proposal prior to the Committee making a final recommendation.
- A significant price reduction is necessary to reduce the incremental cost-effectiveness ratio so that it falls within a range considered to represent acceptable cost-effectiveness when these agents are used for the treatment of rheumatoid arthritis.
6. Context for Decision
Cost-effectiveness reviews are an ongoing part of the management of
the PBS. The outcomes of this review into the cost-effectiveness of
the bDMARDs subsidised via the PBS for the treatment of rheumatoid
arthritis provide a basis for changes to the current funding
arrangements, including patients’ eligibility criteria and/or
price.
7. Sponsor Comments
PharmaLink Pty Ltd [anakinra
(Kineret®)]
Pharmalink is working collaboratively with the PBAC to clarify the
clinical need for anakinra in the treatment of rheumatoid arthritis
and identify the subpopulation of patients who respond to
anakinra.
Pharmalink will work with the PBAC to address the uncertainties
identified in the review, with the goal of retaining PBS-subsidised
access for those patients who respond only to anakinra or for whom
TNF-a inhibitors are contraindicated and for whom no other
therapeutic options are available.
