Infliximab, powder for IV infusion, 100 mg, Remicade®, July 2008
Public summary document for Infliximab, powder for IV infusion, 100 mg, Remicade®, July 2008
Page last updated: 14 November 2008
Public Summary Documents
Product: Infliximab, powder for IV infusion, 100
Sponsor: Schering-Plough Pty Ltd
Date of PBAC Consideration: July 2008
1. Purpose of Application
The submission sought an extension to the current Section 100
rheumatoid arthritis restriction to allow dose escalation to 5
(i) patients who have failed to respond to an initial 3 mg/kg dose (primary non-responders); and
(ii) patients who have responded to treatment at 3 mg/kg but subsequently experienced a disease flare (secondary non-responders).
At the September 2002 meeting, the PBAC rejected an application for
Section 100 listing of infliximab in adults with rheumatoid
arthritis because of uncertain and high cost-effectiveness
At the March 2003 meeting, the PBAC recommended the Section 100 listing of infliximab for the initial and continuing treatment of adults with severe active rheumatoid arthritis who meet certain criteria on a cost-minimisation basis compared with etanercept, which included the infusion administration costs for infliximab. The equi-effective doses are infliximab 3 mg/kg given over 7.25 infusions and etanercept 25 mg twice weekly for 1 year. Infliximab was listed on 1 November 2003.
At the July 2004 meeting, the PBAC recommended that the Section 100 listing for infliximab for the treatment of rheumatoid arthritis be amended to specify a minimum dose of 7.5 mg weekly for the concomitant methotrexate treatment.
Current Interchangeability Rules
Patients are able to swap to an alternate bDMARD without having to experience a disease flare while they continue to respond to therapy. However, a patient cannot trial and fail, or cease to respond to, the same bDMARD more than once. Once a patient has failed treatment 3 times, they must have a 5-year break before they are eligible to commence the next Treatment Cycle.
3. Registration Status
Infliximab is TGA registered for:
- Rheumatoid arthritis in adults. Reduction of signs and symptoms and prevention of structural joint damage (erosions and joint space narrowing) in combination with methotrexate in: patients with active disease despite treatment with methotrexate; patients with active disease who have not previously received methotrexate. Remicade should be given in combination with methotrexate. Efficacy and safety in RA have been demonstrated only in combination with methotrexate.
- Ankylosing spondylitis
- Psoriatic arthritis
- Crohn's disease in adults and in children and adolescents (6 to 17 years)
- Refractory fistulising Crohn's disease
- Ulcerative colitis
4. Listing Requested and PBAC’s View
Section 100 (Highly Specialised Drugs Program) Private
hospital authority required
Patients eligible for treatment with infliximab who do not adequately respond to the initial treatment course can trial one dose escalation of infliximab to 5 mg/kg. Assessment of response is based on the standard criteria for continuing treatment. Response must be measured and submitted to Medicare Australia no later than two weeks prior to the next required dose of infliximab (within 6 weeks of escalated dose).
A patient may qualify to receive up to 24 weeks of continuing treatment at a dose of 5 mg/kg providing they have demonstrated an adequate response to treatment within 6 weeks after dose escalation. Assessment of response is based on the standard criteria for continuing treatment. The patient remains eligible to receive continuing treatment in courses of up to 24 weeks providing they continue to sustain the response.
For PBAC’s view, see Recommendation and Reasons.
The submission nominated etanercept, adalimumab, and rituximab as
For PBAC’s view, see Recommendation and Reasons.
6. Clinical Trials
The basis of the submission was a sub-group analysis of patients in
an uncontrolled single-arm extension of a trial (START), who
received dose escalation of infliximab due to primary or secondary
failure to respond to infliximab 3 mg/kg. The submission compared
infliximab dose escalation with one uncontrolled prospective
consecutive case series of etanercept in patients who failed
infliximab, and one randomised double blind placebo controlled
study of rituximab in patients who were intolerant to or had had
inadequate response to TNF antagonists.
The evaluation also presented two additional trials/studies: an open label multi-centre study of the effectiveness of adalimumab in patients who ceased treatment with infliximab and/or etanercept due to lack of efficacy, and an interrogation of the Stockholm TNFα follow-up registry of patients treated with adalimumab as second line therapy after the secondary loss of efficacy of etanercept or infliximab.
The trials published at the time of submission are listed below:
|Trial ID/First Author
|Protocol title/publication title
|START Rahman MU, et al. 2007
|Double-blinded infliximab dose escalation in patients with rheumatoid arthritis.
|Ann Rheum Dis 66: 1233-1238
|Bombardieri S,et al. 2007
|Effectiveness of adalimumab for rheumatoid arthritis in patients with a history of TNF-antagonist therapy in clinical practice.
|Rheumatol 46: 1191–1199
|Wick MC, et al. 2005
|Adalimumab (Humira) restores clinical response in patients with secondary loss of efficacy from infliximab (Remicade) or etanercept (Enbrel): Results from the STURE registry at Karolinska University Hospital.
|Scand J Rheumatol 34: 353–358
|Buch MH, et al. 2007
|Therapy of patients with rheumatoid arthritis: outcome of infliximab failures switched to etanercept.
|Arth Rheum 57 (3): 448–453
|Cohen SB, et al. 2006
|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.
|Arth Rheum 54: 2793–2806
7. Results of Trials
Infliximab versus etanercept
The key outcomes of the submission’s main analysis comparing infliximab dose escalation (due to primary or secondary failure to respond to 3 mg/kg) in an uncontrolled subgroup of a single arm of the START trial with the single arm of an uncontrolled prospective consecutive case series of etanercept in patients who failed infliximab (Buch 2007), with no common reference are summarised in the tables below:
ACR20 and ACR50 response rate for infliximab 3mg/kg primary and secondary non-responders treated with infliximab dose escalation or etanercept
|Switch to: Infliximab 3mg/kg
|Infliximab dose escalation to 4.5mg/kg (START)
|Etanercept Buch 2007 a
|Responders TSJ n/N (%)
|Responders Adjusted to ACR20 n/N (%) b
|Responders ACR20 n/N (%)
|21/53 (40) d
|30/47 (64) e
|Primary + secondary non-responders
ACR, American College of Rheumatology; TSJ, combined tender joint count and swollen
a responders are patients who achieved response after 12 weeks of etanercept therapy
b converted from number of TSJ responders using the ratio of ACR20 responders to TSJ responders at week 22
c converted using same method as used by submission for adjustment to ACR20. The conversion factor used is 0.4.
d responders are the number of patients who received one dose escalation at week 22 and achieved at least a 20% improvement in the combined number of swollen joints and tender joints at week 30
e responders are the number of patients who received one dose escalation at week 30 or thereafter and achieved at least 20% improvement in the combined number of swollen joints and tender joints. The submission stated the responders were those who received one dose escalation at week 38, Rahman (2007) p3, specifies that secondary non-responders were those who responded at week 22 but later flared and the START trial response criteria measured response at 8 weeks after the previous dose escalation.
The results showed there was a trend for higher response rates in primary infliximab non-responders who subsequently switched to etanercept compared to escalating the dose of infliximab to 4.5mg/kg.
Infliximab versus adalimumab
The results from the indirect comparison with adalimumab (based on Bombardieri 2007 and Wick 2005) showed that among patients who fail to respond to infliximab initially (primary non-responders), the ACR20 response rate is numerically higher in patients switching to adalimumab compared with patients increasing their dose of infliximab to 4.5 mg/kg. However, this difference was not statistically significant.
Infliximab versus rituximab
The results from the indirect comparison of infliximab dose escalation with rituximab showed that the ACR20 response rate among primary and secondary infliximab non-responders is numerically higher among patients switching to rituximab compared with patients increasing their dose of infliximab to 4.5 mg/kg. However, this difference was not statistically significant.
The limited available evidence comparing infliximab dose escalation to the comparators demonstrated a trend to increased frequency of serious adverse events and adverse events leading to discontinuation. The rates of overall adverse events were similar (infliximab dose escalation, 85%, etanercept, 81%, rituximab, 88%).
For PBAC’s comments on these results, see Recommendation and Reasons.
8. Clinical Claim
The submission claimed that dose escalation to 4.5 mg/kg infliximab
was non-inferior in terms of comparative effectiveness and
equivalent in terms of comparative safety compared with etanercept
and rituximab in patients who have not responded to initial
infliximab 3 mg/kg (primary non-responders) and in patients who
have responded to 3 mg/kg and subsequently experienced a flare
The PBAC were concerned that dose escalation of infliximab appeared to be inferior to switching to an alternate bDMARD in primary non-responders.
For PBAC’s view, see Recommendation and Reasons.
9. Economic Analysis
The submission presented a cost minimisation analysis. The
submission estimated the equi-effective doses as infliximab 5 mg/kg
for 6.75 infusions over one year (based on infusions every 8 weeks
over 54 weeks) and etanercept 25 mg twice per week for over one
For PBAC’s view, see Recommendation and Reasons.
10. Estimated PBS Usage and Financial Implications
The submission estimated the financial cost per year to the PBS
minus any savings in use of other drugs to be less than $10 million
in Year 5. The PBAC considered this was likely to be an
11. Recommendation and Reasons
The PBAC noted that the clinical evidence in the START trial
suggests that some patients who do not respond to 3 mg/kg
infliximab will respond to 4.5 mg/kg infliximab. However the PBAC
considered that the clinical benefit was uncertain because of the
very small number of patients in the trial who represent the
population who would be eligible for infliximab through the PBS.
Furthermore, the PBAC considered that the quality of the evidence
presented in the submission was not sufficient to support the
recommendation that infliximab dose escalation to 4.5 mg/kg is
non-inferior to etanercept or rituximab in primary or secondary
non-responders to infliximab 3 mg/kg. The submission’s main
analysis compared infliximab dose escalation in an uncontrolled
subgroup of a single arm of the START trial with the single arm of
an uncontrolled study of etanercept in patients who failed
infliximab (Buch 2007), with no common reference. The submission
also presented an indirect comparison of the single arm of the
START trial with a randomised placebo controlled trial of rituximab
in patients who are intolerant to or have had an inadequate
response to TNF antagonists (Cohen 2006), with placebo as the
common comparator. The PBAC considered that the indirect comparison
with adalimumab, based on Bombardieri 2007 and Wick 2005, was also
relevant despite the submission excluding these studies as the
definition of non-response was not provided. The PBAC noted that
the exclusion of these trials is inconsistent with the
submission’s inclusion of Buch 2007 and Cohen 2006 which also
do not define non-response criteria.
Notwithstanding limitations of the comparisons presented in the submission, the PBAC were concerned that dose escalation of infliximab appeared to be inferior to switching to an alternate bDMARD in primary non-responders. The PBAC noted that the evidence was stronger for secondary non-responders treated with a higher dose of infliximab, but considered that there is uncertainty as to whether a response to the higher dose of infliximab would be maintained over time.
The PBAC considered that if dose escalation to 5 mg/kg infliximab were to be recommended, that it would be reasonable to allow an initial treatment period at the higher dose sufficient for completion of two infusions prior to assessment of response. The submission suggests assessment at 6 weeks, therefore patients would only have had one infusion at the higher dose. The Committee noted the submission’s request that dose escalation of infliximab be counted as one trial of a bDMARD within a treatment cycle, but considered that this request needed further examination in the context of a broader review of PBS subsidised bDMARDs.
The PBAC sought clinical opinion during the Hearing, which suggested that clinicians would prefer the option of initiating patients on the 5 mg/kg dose rather than commencing on 3 mg/kg and increasing to 5 mg/kg if there was no response. The PBAC noted that 5 mg/kg is the dose of infliximab used for all other approved indications including Crohn disease, ankylosing spondylitis, and psoriasis. However, the PBAC recognised that the current TGA indication for infliximab in rheumatoid arthritis stipulates that patients initiate on a dose of 3 mg/kg and increase in increments of 1.5 mg/kg to a maximum of 7.5 mg/kg.
Despite clinical and anecdotal evidence that a proportion of patients do not respond to infliximab 3 mg/kg, Medicare Australia provided data to the PBAC that indicated that the vast majority of all patients commenced on PBS infliximab continue on with treatment. Therefore the clinical need for the availability of infliximab dose escalation in the PBS population is somewhat uncertain.
The PBAC acknowledged that for a proportion of patients the availability of a bDMARD that can be administered as an infusion is preferable to subcutaneous administration, but considered that abatacept and rituximab offer alternative intravenous treatments in this group of patients.
The PBAC therefore rejected the application on the basis of uncertain clinical effectiveness and consequently uncertainty in establishing cost-minimisation against existing therapies.
12. 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.
13. Sponsor’s Comment
The sponsor chose not to comment.