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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).
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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.
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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.
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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.
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