Etoricoxib, tablet, 30 mg, 60 mg, Arcoxia®, July 2008
Public summary document for Etoricoxib, tablet, 30 mg, 60 mg, Arcoxia®, July 2008
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Public Summary Documents
Product: Etoricoxib, tablet, 30 mg, 60 mg,
Arcoxia®
Sponsor: Merck Sharp & Dohme (Australia) Pty
Limited
Date of PBAC Consideration: July 2008
1. Purpose of Application
The submission requested a restricted benefit listing for the
symptomatic treatment of osteoarthritis.
2. Background
A listing for the symptomatic treatment of osteoarthritis was first
requested at the March 2004 meeting. The Pharmaceutical Benefits
Advisory Committee (PBAC) rejected the\
submission on the grounds of uncertainty over the comparative
safety claim, although the claim of superiority over traditional
NSAIDs in terms of reducing perforations, ulcers and bleeds (PUBs)
overall
was accepted.
At the July 2007 meeting, the PBAC rejected a submission for a
restricted benefit listing for etoricoxib for the symptomatic
treatment of arthritis (30 mg & 60 mg) on the basis of
uncertain comparative safety in terms of hypertension. The PBAC
noted that there had been a delay in the Therapeutic Goods
Administration (TGA) approval process for etoricoxib 30 mg and thus
agreed with the sponsor’s request that this strength not be
considered at this time.
(See also PBAC Public Summary Document – July
2007).
3. Registration Status
Etoricoxib 60 mg, 90 mg and 120 mg tablets were TGA registered on 30 September 2002 and 30 mg tablets on 11 April 2008 for the following indications:
- Symptomatic treatment of the signs and symptoms of osteoarthritis (OA)
- Treatment of acute gouty arthritis
- Treatment of acute pain, including that related to primary dysmenorrhea and minor dental procedures.
4. Listing Requested and PBAC’s View
Note: The use of etoricoxib for the treatment of
the following conditions is not subsidised through the PBS:
(a) acute pain
(b) soft tissue injury;
(c) arthrosis without inflammatory component.
Restricted Benefit
Symptomatic treatment of osteoarthritis
Note: No applications for increased maximum
quantities and/or repeats will be authorised
See Recommendation and Reasons for PBAC’s
view.
5. Clinical Place for the Proposed Therapy
Osteoarthritis is a chronic and progressive condition. Etoricoxib
would provide an alternative selective cyclooxygenase-2 (Cox-2)
inhibitor drug for treatment of patients with symptomatic
osteoarthritis. (A selective cyclooxygenase-2 (Cox-2) inhibitor is
a form of Non-steroidal anti-inflammatory drug (NSAID) that
inhibits the COX-2 enzyme; an enzyme involved in inflammation and
pain).
6. Comparator
The submission nominated celecoxib (200 mg) as the main comparator.
The PBAC accepted that celecoxib is an appropriate comparator for
the requested restricted benefit listing of etoricoxib for the
symptomatic treatment of osteoarthritis.
7. Clinical Trials
The basis of the re-submission was:
- one randomised trial (P007) comparing the effectiveness of etoricoxib 30 mg to etoricoxib 60 mg and placebo;
- two randomised trials (P076/P077) directly comparing the effectiveness of etoricoxib 30 mg to celecoxib 200 mg (There are no trials directly comparing the effectiveness and safety of the 60 mg dose of etoricoxib and the 200 mg dose of celecoxib);
- an indirect Bayesian meta-analysis involving 21 trials indirectly comparing the efficacy of etoricoxib 30 mg and 60 mg doses with celecoxib 200 mg via the common reference of traditional NSAIDs (tNSAIDs); and
- to assess hypertension-related safety, two randomised trials directly comparing etoricoxib 30 mg with celecoxib 200 mg (P076/P077) as well as four supportive indirect safety analyses comparing etoricoxib with celecoxib via the “common reference” of a heterogeneous group of tNSAIDs (three analyses conducted for the FDA and one conducted for the re-submission).
The key trials published at the time of submission are as follows:
| Trial | Protocol title/Publicaton title | Publicaton citation |
| Etoricoxib | ||
| P076 P077 | Publication (for both P076 and P077): Efficacy and safety of etoricoxib 30 mg and celecoxib 200 mg in the treatment of OA in two identically designed, randomised, placebo-controlled, non-inferiority studies. | Bingham C.O. et al, 2007. Rheumatology;46:pp496-507 |
| P066 MEDAL Program | Cardiovascular outcomes with etoricoxib and diclofenac in patients with OA and RA arthritis in the Multinational Etoricoxib and Diclofenac Arthritis Long-term (MEDAL) programme: a randomised comparison. | Cannon CP et al, (2006). Lancet. 368(9549): pp1771-81 |
| P007 | P007 Merck CSR, MRL Clinical Study Report (P007) Etoricoxib in the treatment of OA over 52-weeks: A double-blind, active-comparator controlled trial. | Curtis et al (2005). BMC Musculoskeletal Disorders; 6(58), p2489 |
| Results of a randomized, dose-ranging trial of etoricoxib in patients with OA. | Gottesdiener et al., (2002). Rheumatology ;41(9): pp1052-61 | |
8. Results of Trials
The key results of the key trials are summarised below.
Trial P007: etoricoxib 30 mg versus etoricoxib 60
mg Both the 30 mg and 60 mg doses of etoricoxib
demonstrated a statistically significant and a pre-specified
clinically important reduction (≥10mm on a VAS 100 mm scale) in
the primary outcome of pain compared to placebo. Reduction in pain,
in patients treated with 60 mg etoricoxib, was significantly
greater, although not to a clinically important extent, compared to
pain reduction in patients treated with 30 mg etoricoxib
(Least-Squares Mean Change (The time-weighted average change from
baseline for each primary outcome was analysed using an analysis of
covariance (ANCOVA) model with treatment and primary OA joint as
the main factors (fixed effects) and baseline value as the
covariate: a negative score indicates improvement.) :
-8.44mm; 95% CI: -14, -2.87; p=0.003).
Trial P076: etoricoxib 30 mg versus celecoxib 200
mg The results of trials P076 and P077 demonstrated that
treatment with etoricoxib 30 mg appeared to be no worse (based on a
pre-specified non-inferiority margin of 10mm) than treatment with
celecoxib 200 mg in terms of reducing pain, improving function and
patient global assessment of disease status (PGADS).
The results from the individual trials were consistent with those
from a pooled analysis of both P076 and P077 data conducted for the
re-submission. Using a random effects model, etoricoxib 30 mg was
no worse (pre-specified non-inferiority margin of 10mm) compared to
celecoxib 200 mg in terms of reducing pain (weighted mean
difference, WMD: -1.43; 95% CI: -4.62, 1.76), improving physical
function (WMD: -0.87; 95% CI: -3.89, 2.04) and improving Patient
Global Assessment of Disease Status , PGADs (WMD: -1.92; 95% CI:
-5.95, 2.10).
The re-submission presented new and extensive hypertension safety
data, as follows:
(1) Key hypertension safety analysis 1 (Etoricoxib trials: P076 and
P077): direct comparison of hypertension safety between etoricoxib
30 mg and celecoxib 200 mg using the two head-to-head trials;
(2) Supportive hypertension meta-analysis 2 (OA Development Program
etoricoxib trials: P073,P007, P071, P018, P019, P010, P805, &
MEDAL Program trials (EDGE, EDGE II and MEDAL trials); celecoxib
trials: Geba et al, Schnitzer et al & Singh et al (SUCCESS)): a
meta-analysis indirectly comparing the blood pressure safety
profiles of etoricoxib (30 mg and 60 mg doses) and celecoxib 200 mg
via tNSAIDs as the common comparator;
(3) Supportive FDA hypertension analyses (FDA ACM Background
Package April 2007, Response to the FDA Question 6 January 2007,
additional analysis conducted for the submission requested by
MSDA)
There was an increased risk of hypertension-related adverse events
(Hypertension-related adverse events included events captured under
the clinical term “hypertension” (not clearly defined
in the re-submission) and events associated with a systolic blood
pressure ≥180mmHg or a diastolic blood pressure of ≥110mmHg.)
associated with etoricoxib 30 mg compared to celecoxib 200 mg. The
results raised concerns regarding an inferior hypertension safety
profile associated with etoricoxib compared to celecoxib.
The results from the individual direct trials demonstrate that
patients in the etoricoxib 30mg treatment arm experienced a higher
mean increase from baseline in systolic blood pressure than
patients in the celecoxib 200mg treatment arm. The results of the
mean changes in systolic blood pressure for etoricoxib 30 mg and
celecoxib 200 mg or trial P077demonstrated that the proportion of
patients who experienced systolic blood pressure end points (as
defined in the MEDAL Program trials) in the etoricoxib 30 mg
treatment arm (3.7%) was more than double that in the celecoxib 200
mg treatment arm (1.6%). In trial P076, this difference was less
remarkable (etoricoxib 30 mg, 2.6%; celecoxib 200 mg, 2.1%).
Combined data from both trials indicated that this clinically
important outcome - the proportion of patients experiencing
consecutive systolic blood pressure measurements >140 mmHg and
> 20 mmHg change from baseline - in the etoricoxib 30 mg arm
(3.2%) was approximately double that of the celecoxib 200 mg
treatment arm (1.9%). The small number of patients experiencing
diastolic blood pressure events made any meaningful comparison
difficult.
Trials P076 and P077: Proportion of patients exceeding
predefined limits of change (as defined in the MEDAL Program
trials) for systolic and diastolic blood pressure-Parts I and II
(26 weeks)
| Trial | Vital Sign (units) | Predefined limit of Change | Etoricoxib 30mg (N=244) | Celecoxib 200mg (N=247) | Absolute difference Etoricoxib vs Celecoxib |
| n/N (%) | n/N (%) | (%) | |||
| P076 | Systolic BP (mmHg) | Consecutive Values >140 and Increases >20 | 6/229 (2.6) | 5/237 (2.1) | 0.5 |
| Diastolic BP (mmHg) | Consecutive Values >90 and Increases >15 | 0/229 (0.0) | 0/237 (0.0) | 0.0 | |
| P077 | Systolic BP (mmHg) | Consecutive Values >140 and Increases >20 | 9/243(3.7) | 4/245 (1.6) | 2.7 |
| Diastolic BP (mmHg) | Consecutive Values >90 and Increases >15 | 1/243 (0.4) | 0/245 (0.4) | 0.0 | |
| n/N= Number of patients meeting the pre-defined limit criteria/total number of patients with valid values for the vital sign test. A patient may have exceeded the predefined limits of change for more than one parameter and may appear in more than one category. | |||||
For PBAC’s comments on these results, see the
Recommendations and Reasons.
9. Clinical Claim
The re-submission claimed that etoricoxib (1) was no worse in terms
of effectiveness with possibly better efficacy associated with the
60 mg dose, and (2) in terms of safety, as having
(i) similar changes from baseline in systolic blood pressure and
diastolic blood pressure; and
(ii) a higher but statistically insignificant rate of
discontinuation due to hypertension-related adverse events, and a
higher statistically significant rate of hypertension- related
adverse events.
The PBAC agreed that non-inferiority of etoricoxib 30 mg and 60 mg
to celecoxib 200 mg was demonstrated in terms of clinical
effectiveness. However, the PBAC remained of the view that the
non-inferiority of etoricoxib and celecoxib in terms of safety was
not established.
For PBAC’s views, see the Recommendations and
Reasons.
10. Economic Analysis
The submission presented a cost minimisation analysis.
For PBAC’s views, see the Recommendations and
Reasons.
11. Estimated PBS Usage and Financial Implications:
The financial cost per year to the PBS was estimated to be less
than $10 million per year in Year 5.
12. Recommendation and Reasons:
The PBAC did not accept the sponsor’s claim that there is a
clinical need for an additional COX-2 selective agent on the PBS
for the symptomatic treatment of osteoarthritis, as there are a
number of agents currently available.
The PBAC accepted that celecoxib is an appropriate comparator for
the requested restricted benefit listing of etoricoxib for the
symptomatic treatment of osteoarthritis. The PBAC agreed that
non-inferiority of etoricoxib 30 mg and 60 mg to celecoxib 200 mg
was demonstrated in terms of clinical effectiveness. The trial P007
comparing etoricoxib 30 and 60 mg to placebo, and trials P076 and
P077 comparing etoricoxib 30 mg to celecoxib 200 mg demonstrated
that treatment with etoricoxib 30 mg appears to be no worse than
treatment with celecoxib 200 mg in terms of reducing pain,
improving function and patient global assessment of disease
status.
However the PBAC remained of the view that the non-inferiority of
etoricoxib and celecoxib in terms of safety was not established,
noting that the re-submission presented new data on comparative
hypertension safety, as follows:
1. Key hypertension safety analysis: direct comparison of
hypertension safety between etoricoxib 30 mg and celecoxib 200 mg
using two head-to-head trials;
2. Supportive hypertension meta-analysis: a meta-analysis
indirectly comparing the blood pressure safety profiles of
etoricoxib (30 mg and 60 mg doses) and celecoxib 200 mg via
traditional NSAIDs as the common comparator;
3. Supportive FDA hypertension analyses
The Committee agreed that the results of the direct trials (which
represent the most scientifically robust basis in the
re-submission) presented confirm the increased risk of
hypertension-related adverse events and elevated blood pressure
associated with etoricoxib 30 mg compared to celecoxib 200 mg and
that the re-submission does not provide clinical trial evidence to
resolve the primary concern behind the PBAC rejection of the July
2007 application, which was in relation to the higher risk of
increased systolic blood pressure and hypertension-related adverse
events of etoricoxib compared to celecoxib. The Committee also
agreed that the indirect safety analyses were flawed and had many
limitations making interpretability difficult.
The demonstrated increased risk raises further concerns regarding
the requested listing of the higher dose (60 mg) of etoricoxib
given the dose-related blood pressure effects of etoricoxib.
Although the Pre-Sub-Committee response states that a listing of
only 30 mg dose would be acceptable to the sponsor, the 30 mg dose
is the recommended initial dose in the product information and
there is likely to be a proportion of patients for whom the 30 mg
dose would not provide a sufficient treatment effect.
The PBAC further noted that the key trial populations were
non-hypertensive or had adequately controlled hypertension at
baseline, and hence it is unclear whether the results are
applicable to the population for whom PBS listing of etoricoxib is
sought.
Thus the PBAC did not accept that non-inferiority of etoricoxib 30
mg or 60 mg to celecoxib 200 mg was demonstrated and agreed that
the cost-minimisation approach taken in the re-submission was not
adequately justified.
The PBAC acknowledged the sponsor’s initiative in the
planning of a quality use of medicines (QUM) program for
etoricoxib, however no robust evidence was presented in the
re-submission to support the claim that, under such an approach,
the impact of the demonstrated increased hypertensive risk with
etoricoxib will become clinically unimportant.
Overall, the PBAC rejected the submission on the basis of a lack of
demonstrated clinical need for etoricoxib in the context of an
inferior safety profile in terms of hypertensive related adverse
events, compared to celecoxib.
Recommendation
Reject
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
While the PBAC rejected the submission in the context of an
inferior safety profile in terms of hypertensive related adverse
events, compared to celecoxib, other analyses provided to the PBAC
in the submission demonstrates that in patients with OA, the effect
of etoricoxib (30mg and 60mg) on blood pressure is generally
similar to that of non-selective NSAIDs such as the most commonly
used NSAID in Australia, diclofenac. Following its review of NSAIDs
in 2006, the TGA now requires the Product Information documents of
all registered prescription-selective NSAIDs reviewed to contain
statements to the effect that "NSAIDs may lead to the onset of new
hypertension or worsening of pre-existing
hypertension….".
The sponsor proposed to implement a quality use of medicines (QUM)
approach to support the appropriate use of etoricoxib; actively
advocating for best practice for the management of OA, including
guidelines recommendation of the type of NSAIDs that are
appropriate for individual patients.
