Certolizumab pegol for treating rheumatoid arthritis after inadequate response to a TNF-alpha inhibitor

Evidence-based recommendations on certolizumab pegol (Cimzia) for treating severe active rheumatoid arthritis in adults who have had a tumour necrosis factor-alpha inhibitor.

# Recommendations
Certolizumab pegol, in combination with methotrexate, is recommended as an option for treating active rheumatoid arthritis in adults whose disease has responded inadequately to, or who cannot tolerate, other disease-modifying antirheumatic drugs (DMARDs) including at least 1 tumour necrosis factoralpha (TNFalpha) inhibitor, only if:
disease activity is severe and
rituximab is contraindicated or not tolerated and
the company provides certolizumab pegol with the agreed patient access scheme.
Certolizumab pegol, as monotherapy, is recommended as an option for treating active rheumatoid arthritis in adults whose disease has responded inadequately to, or who cannot tolerate, other DMARDs including at least 1 TNFalpha inhibitor, only if:
disease activity is severe and
rituximab therapy cannot be given because methotrexate is contraindicated or not tolerated and
the company provides certolizumab pegol with the agreed patient access scheme.
Continue treatment only if there is at least a moderate response measured using European League Against Rheumatism (EULAR) criteria at 6 months. After an initial response within 6 months, withdraw treatment if at least a moderate EULAR response is not maintained.
Take into account any physical, sensory or learning disabilities, or communication difficulties that could affect the responses to the disease activity score and make any appropriate adjustments.
This guidance is not intended to affect the position of patients whose treatment with certolizumab pegol was started within the NHS before this guidance was published. Treatment of those patients may continue without change to whatever funding arrangements were in place for them before this guidance was published until they and their NHS clinician consider it appropriate to stop.# The technology
Description of the technology
Certolizumab pegol (Cimzia, UCB Pharma) is a recombinant humanised antibody Fab' fragment against tumour necrosis factor-alpha (TNFalpha) and is conjugated to polyethylene glycol (PEG). TNFalpha is a pro-inflammatory mediator that is partly responsible for damage to the joints in rheumatoid arthritis.
Marketing authorisation
Certolizumab pegol in combination with methotrexate (MTX) has a marketing authorisation in the UK for 'the treatment of moderate to severe, active rheumatoid arthritis in adult patients when the response to disease-modifying antirheumatic drugs (DMARDs) including MTX, has been inadequate'. Certolizumab pegol can be given as 'monotherapy in case of intolerance to MTX or when continued treatment with MTX is inappropriate'.
Certolizumab pegol also has a marketing authorisation in combination with MTX for 'the treatment of severe, active and progressive rheumatoid arthritis in adults not previously treated with MTX or other DMARDs', but this is not within the remit of this technology appraisal.
Adverse reactions
Certolizumab pegol is contraindicated in people with active tuberculosis or other severe infections, and in people with moderate or severe heart failure. The summary of product characteristics lists no adverse reactions as very common but notes that in clinical trials the most common adverse reactions were bacterial and viral infections. For full details of adverse reactions and contraindications see the summary of product characteristics.
Recommended dose and schedule
The recommended starting dose of certolizumab pegol for adult patients is 400 mg (given as 2 subcutaneous injections of 200 mg each) at weeks 0, 2 and 4. After the starting dose, the recommended maintenance dose of certolizumab pegol is 200 mg every 2 weeks. Once clinical response is confirmed, an alternative maintenance dosing of 400 mg every 4 weeks can be considered. MTX should be continued during treatment with certolizumab pegol when appropriate.
Price
The net price of certolizumab pegol is 357.50 per 200mg prefilled syringe (excluding VAT; 'British national formulary'  edition 71). The company has agreed a patient access scheme with the Department of Health. In the scheme, the first 12 weeks of therapy (currently 10 pre-loaded syringes of 200 mg each) with certolizumab pegol are free of charge. The acquisition cost is 6,793 in the first year of treatment and then 9,295 per year. The Department of Health considered that this patient access scheme does not constitute an excessive administrative burden on the NHS.# Evidence
The appraisal committee (section 6) considered evidence submitted by UCB Pharma and a review of this submission by the evidence review group (ERG). See the committee papers for full details of the evidence.# Committee discussion
The appraisal committee reviewed the data available on the clinical and cost effectiveness of certolizumab pegol, having considered evidence on the nature of rheumatoid arthritis and the value placed on the benefits of certolizumab pegol by people with the condition, those who represent them, and clinical experts. It also took into account the effective use of NHS resources.

# Clinical need and practice
The committee understood that the remit is to appraise certolizumab pegol when the response to other disease-modifying antirheumatic drugs (DMARDS), including a tumour necrosis factoralpha (TNFalpha) inhibitor, has been inadequate. It noted existing NICE guidance at this point in the treatment pathway (NICE technology appraisal guidance on adalimumab, etanercept, infliximab, rituximab and abatacept for rheumatoid arthritis, golimumab for rheumatoid arthritis and tocilizumab for rheumatoid arthritis). These recommend rituximab plus methotrexate after an inadequate response or intolerance to other DMARDs, including at least 1 TNFalpha inhibitor. The committee was also aware that the guidance recommends adalimumab, etanercept, infliximab, abatacept, tocilizumab and golimumab (each with methotrexate) as options, when rituximab (plus methotrexate) is contraindicated or not tolerated and adalimumab and etanercept monotherapy as alternative options if rituximab therapy cannot be given because methotrexate is contraindicated or not tolerated. The committee heard from the patient experts that response to treatment is difficult to predict, because responses to biological DMARDs (bDMARDs) differ between people. The clinical expert emphasised the importance of a range of options for bDMARD treatments, particularly when rituximab plus methotrexate cannot be offered because of well-documented risks of adverse events occurring (for example, after infusion). The committee concluded that an additional treatment option for rheumatoid arthritis that has not responded to a TNFalpha inhibitor would be valued by both patients and clinicians.
The committee was aware that the marketing authorisation covers the use of certolizumab pegol in moderate to severe disease. It was reminded that NICE technology appraisal guidance on adalimumab, etanercept, infliximab, certolizumab pegol, golimumab, tocilizumab and abatacept for rheumatoid arthritis not previously treated with DMARDs or after conventional DMARDs have failed recommends that treatment with a bDMARD should only be started when disease is severe, that is a disease activity (DAS28) score of more than 5.1. The committee understood that, at the point in the treatment pathway when treatment with the first bDMARD has not given an adequate response, severity of disease would have already been established. The committee was aware that there is a group of patients whose DAS28 score may be more than 5.1 when starting treatment with a first bDMARD, but whose DAS28 score may subsequently be less than 5.1 even though the disease has not adequately responded to the first bDMARD. The committee understood that this group would be small. It also understood from the consultation comments that this group would be considered to have severe disease, because the disease has already been confirmed as severe at an earlier point in the treatment pathway. The committee further noted that NICE technology appraisal guidance on adalimumab, etanercept, infliximab, rituximab and abatacept for rheumatoid arthritis and golimumab for rheumatoid arthritis do not define disease severity in the recommendations. Therefore, the committee did not consider it necessary to define disease severity using the DAS28 score measure when starting a second bDMARD.

# Decision problem
The committee considered the comparators for certolizumab pegol set out in the scope. It noted that the comparator was rituximab plus methotrexate. It was aware that, in line with existing NICE technology appraisal guidance (see section 4.1), alternative bDMARD treatment options were listed as comparators for those people for whom rituximab or methotrexate are contraindicated or withdrawn. The committee noted that the company had presented the evidence for 3 distinct populations, all of whom have been treated with a TNFalpha inhibitor:
people for whom rituximab is contraindicated or not tolerated
people for whom methotrexate is contraindicated or not tolerated
people for whom rituximab plus methotrexate is a treatment option.
The committee concluded that it was appropriate to consider the 3 groups as distinct from each other, and went on to consider the company's choice of comparators for each group. The committee noted that the company compared treatment sequences for the defined populations. The 3 tables below, show the sequences presented by the company. For the populations for whom methotrexate or rituximab is contraindicated, the sequences were of equal length and the comparator bDMARDs were:
Abatacept, adalimumab, etanercept, golimumab, infliximab and tocilizumab (each plus methotrexate) when rituximab is contraindicated or not tolerated (table 1).
Adalimumab monotherapy, etanercept monotherapy or tocilizumab monotherapy when rituximab therapy cannot be given because methotrexate is contraindicated or not tolerated (table 2).
Line of therapy
Sequence with certolizumab pegol (plus methotrexate)
Comparator sequence bDMARD (plus methotrexate)
st
Certolizumab pegol
Comparator biological
nd
Methotrexate plus hydroxychloroquine plus sulfasalazine
Methotrexate plus hydroxychloroquine plus sulfasalazine
rd
Leflunomide
Leflunomide
th
Gold injection
Gold injection
th
Ciclosporin
Ciclosporin
th
Azathioprine
Azathioprine
th
Palliative care
Palliative care
Line of therapy
Sequence with certolizumab pegol (monotherapy)
Comparator sequence bDMARD (monotherapy)
st
Certolizumab pegol
Comparator biological
nd
Leflunomide
Leflunomide
rd
Gold injection
Gold injection
th
Ciclosporin
Ciclosporin
th
Azathioprine
Azathioprine
th
Palliative care
Palliative care
Line of therapy
Sequence with certolizumab pegol and bDMARDs (plus methotrexate)
Comparator sequence bDMARD (plus methotrexate)
st
Certolizumab pegol
Rituximab
nd
Rituximab
Tocilizumab
rd
Tocilizumab
Abatacept
th
Abatacept
Methotrexate plus hydroxychloroquine plus sulfasalazine
th
Methotrexate plus hydroxychloroquine plus sulfasalazine
Non-biological (weighted mix of leflunomide, gold, azathioprine and ciclosporin)
th
Non-biologic (weighted mix of leflunomide, gold, azathioprine and ciclosporin)
Palliative care
th
Palliative care
The committee accepted the sequences for people for whom rituximab or methotrexate were contraindicated or not tolerated. It noted that for people for whom rituximab is a treatment option, the company compared treatment sequences of different lengths. The sequence containing certolizumab pegol placed certolizumab pegol before rituximab and therefore was not a strict comparison with rituximab because certolizumab pegol did not replace it, as with the other populations defined in the scope (see section 4.3). The committee considered that the sequences included treatments that would be offered to people whose disease has been classified as severe at the start of a first biological treatment. It recognised that the data provided by the company included people with moderate to severe disease, however the company did not separately compare treatment sequences for a population with moderate disease activity only. The committee therefore agreed it should focus on people with severe disease activity.
The committee heard evidence from the clinical expert on the use of biosimilar bDMARDs in clinical practice. It heard that infliximab biosimilars are not used in rheumatology and that the etanercept biosimilar has only been launched recently. It also heard that the etanercept biosimilar should be used in preference to its originator because it has lower acquisition costs. The committee concluded that, because the etanercept biosimilar is being used in clinical practice, it was appropriate to consider it in its decision-making.

# Clinical effectiveness
The committee considered the company's clinical evidence and accepted that the results showed that certolizumab pegol was more clinically effective than placebo. It understood that the only evidence available on the comparative effectiveness of certolizumab pegol and the bDMARDs was from the company's mixed treatment comparisons. The committee heard from the evidence review group (ERG) that there were problems with the methods used for these comparisons. In its response to consultation, the company acknowledged that there was heterogeneity between the studies and it provided a random-effects network meta-analysis to compare with its original fixed-effect network meta-analysis. The results from these analyses are academic in confidence and cannot be included here. The guide to the processes of technology appraisal states that in the interests of public transparency, data marked as confidential should be kept to an absolute minimum. Although it disagrees with the company assertion that including the analysis results would inhibit publication elsewhere, NICE considers it unreasonable to delay the appraisal and access for patients to negotiate further confidentiality lifting with the company, especially as the results were not fundamental to the committee's decision. In addition, while the point estimates from the network meta-analyses were marked as academic-in-confidence, the conclusions were presented publically and showed that the mean effect sizes from the random-effects model were equal to those of the fixed-effects model. The committee concluded that there are uncertainties in the estimates from the methods used and it could not reliably conclude whether certolizumab pegol was more clinically effective than the comparator bDMARDs on the basis of the mixed treatment comparisons presented by the company. The committee reasoned that certolizumab pegol has a similar mechanism of action to other TNFalpha inhibitors, therefore it was plausible to assume that it would have comparative efficacy to other bDMARDs. This reasoning was strengthened when the committee heard from the clinical expert that certolizumab pegol is already in use in clinical practice and is not considered to be better or worse than other TNFalpha inhibitors. The committee concluded that certolizumab pegol has a similar efficacy to other available bDMARDs

# Cost effectiveness
The committee considered the cost-effectiveness evidence for the 3 populations defined in the company's submission (see section 4.1).

## People for whom rituximab or methotrexate are contraindicated or not tolerated
The committee was aware of its conclusion on the efficacy of certolizumab pegol and other bDMARDs (see section 4.6), It queried the base-case incremental cost-effective ratios (ICERs) in the company's submission for the populations of people for whom either rituximab or methotrexate are contraindicated or not tolerated. It would have expected to see similar quality-adjusted life year (QALY) gains to other bDMARDs, but the incremental QALY gain for certolizumab pegol plus methotrexate and certolizumab pegol as monotherapy, were 0.260 for both populations. The committee noted that the company stated there was a lack of comparative evidence in the population who have had TNFalpha inhibitors before and therefore had to place assumptions on comparative effectiveness for the comparator bDMARDs. Therefore, the model assumed that the efficacy of adalimumab, etanercept and infliximab were equivalent to golimumab. The efficacies of adalimumab monotherapy and etanercept monotherapy were modelled using the effect size estimates for golimumab compared with certolizumab pegol (both in combination with methotrexate) from the network meta-analysis. The committee noted that these assumptions were not applied to certolizumab pegol.
The committee then considered the ERG's scenario analysis in which it assumed that certolizumab pegol had equal efficacy to etanercept, adalimumab and infliximab (all plus methotrexate) for people for whom rituximab is contraindicated or not tolerated. The ERG also assumed that certolizumab pegol monotherapy had equal efficacy to etanercept and adalimumab monotherapies for people for whom methotrexate was contraindicated or not tolerated. The committee was aware that the etanercept biosimilar had been included in this sequence and agreed that this was appropriate. The committee noted for these equal length sequence analyses, that the ICERs for certolizumab pegol with methotrexate and as monotherapy were dominated; that is, certolizumab pegol plus methotrexate was more expensive but just as effective as the comparator bDMARDs. When the committee looked at the incremental increase in total costs between certolizumab pegol and the etanercept biosimilar it noted that there was very little difference so equivalence among the bDMARDs could be accepted. The committee considered the ICERs that incorporated confidential patient access schemes for abatacept and tocilizumab, the results of which cannot be shown here. Even when these schemes were taken into account, the committee noted that there were similarities in effects and costs and so concluded that certolizumab pegol plus methotrexate, or as monotherapy, can be considered a cost-effective use of NHS resources for people for whom rituximab or methotrexate are contraindicated or not tolerated.

## People for whom rituximab plus methotrexate is a treatment option
The committee had concerns about the company's approach to evaluating the cost effectiveness of certolizumab pegol plus methotrexate for this population. In particular, it was not persuaded that an intervention treatment sequence containing certolizumab pegol and 6 other treatments should be compared with the same sequence without certolizumab pegol (see section 4.4). The committee was aware from past technology appraisals that using different sequence lengths can increase modelling uncertainties. It heard from the ERG that the company's model may not be appropriate for comparing sequences of different lengths and this point was highlighted in the ERG's exploratory analysis in which the use of the same model type resulted in some counterintuitive results; the clinical benefit (shown by the QALY gain) appeared to be greater if a person had received rituximab plus methotrexate than if a person had received both certolizumab pegol plus methotrexate and rituximab plus methotrexate. In addition the committee also understood that not all possible treatment sequences for this population had been included in the company's analysis. It noted that, to address this, the ERG had included 2 additional sequences in its exploratory analyses, in which certolizumab pegol plus methotrexate was placed after, and instead of, rituximab plus methotrexate. The committee noted that, after consultation, the company had accepted the relevance of the replacement sequence (that is, instead of rituximab plus methotrexate), but did not consider the sequence of certolizumab pegol after rituximab to be within the scope of the appraisal. The committee agreed with this but commented that placing certolizumab pegol plus methotrexate before rituximab plus methotrexate was also unsatisfactory (see section 4.4). It concluded that treatment sequences of the same length are preferable because they are subject to less uncertainty and that its focus should be on the sequence in which certolizumab pegol plus methotrexate replaces rituximab plus methotrexate.
In the revised base-case analysis submitted by the company after consultation, the committee understood that the company had accepted most of the ERG's preferred assumptions, except treatment duration for biological therapies, and the retreatment interval for rituximab. The committee noted that these were key drivers of cost effectiveness. It concluded that each of these should be examined before considering the ICERs for its preferred treatment sequence.
The company provided evidence from 2 studies to support an assumption of equal treatment duration for all biological therapies. A study by Ramiro et al. (2015) provided the evidence for a longer treatment duration with TNFalpha inhibitors compared with nonTNFalpha inhibitors, whereas a study by Du Pan et al. (2012) provided evidence for a shorter treatment duration with TNFalpha inhibitors compared with nonTNFalpha inhibitors. The committee was not persuaded that this opposing evidence should be interpreted as a basis for equal treatment duration. Also, it was not persuaded that these sources of evidence were methodologically stronger than the source preferred by the ERG (the REFLEX extension trial). In the Ramiro et al. (2015) trial, more people received a TNFalpha inhibitor than a nonTNFalpha inhibitor. Also, this study was done in the USA where prescription patterns, reimbursement decisions and patients' comorbidities differ from England. The committee had fewer concerns with the Du Pan et al. (2012) study because it had enrolled more comparable numbers of people on TNFalpha and nonTNFalpha inhibitors. Although the committee acknowledged the company's concerns that trial conditions may not represent clinical practice, it regarded the evidence for rituximab, the comparator of interest, to be superior to that for a collection of nonTNFalpha inhibitor technologies. The committee concluded that the data from the extension phase of the REFLEX trial provided the most appropriate source of evidence for treatment duration.
The committee considered the most plausible assumption for the retreatment interval of rituximab in the model. It noted that the summary of product characteristics for rituximab states that the 'need for further courses should be evaluated 24 weeks after the previous course', but did not consider that this was the same as specifying a 6month retreatment interval. It also noted that the committee had previously discussed this assumption in NICE's technology appraisal guidance on adalimumab, etanercept, infliximab, rituximab and abatacept for rheumatoid arthritis, and concluded that treatment was unlikely to be as frequent as every 6 months for every person receiving rituximab. It therefore preferred the ERG's value of 10.09 months, which was sourced from the REFLEX trial. The committee considered that it was appropriate to use available trial evidence for rituximab to inform this assumption, and concluded that it was appropriate to use a retreatment interval for rituximab of 10.09 months.
In line with its conclusion about treatment sequences (see section 4.4), the committee considered the ICERs when certolizumab pegol plus methotrexate was placed in a sequence instead of rituximab plus methotrexate. The company's base-case estimate for this comparison was in excess of 130,000 per QALY gained. However, the committee recognised that its preferred assumptions for the treatment duration for bDMARDs and the rituximab retreatment interval were not incorporated in this estimate. When these preferred assumptions were included, certolizumab pegol plus methotrexate was dominated by rituximab plus methotrexate. This analysis did not take into account the confidential patient access scheme discount for tocilizumab, a treatment included in the treatment sequence after rituximab. When the confidential discount for tocilizumab was included, certolizumab pegol plus methotrexate was still dominated. In summary, the committee concluded that certolizumab pegol plus methotrexate could not be considered a cost-effective use of NHS resources when rituximab plus methotrexate is a treatment option. For completeness, the committee looked at the elongated sequence, in which certolizumab pegol plus methotrexate was placed before rituximab plus methotrexate, which the committee had rejected earlier (see section 4.4 and section 4.10). The committee concluded that, with its preferred assumptions this sequence was still dominated and therefore was not a cost-effective use of NHS resources.

# Equality issues
The committee heard from the British Society of Rheumatology that certolizumab pegol may be used in pregnancy and that this was a potential equality issue. The committee was aware that the use of certolizumab pegol in pregnancy was outside the marketing authorisation. Because the committee makes recommendations within a technology's marketing authorisation, it could not consider including certolizumab pegol for use in pregnancy in its final recommendations. The committee concluded that it did not need to change its recommendations.

# Innovation
The company stated that not all the benefits of certolizumab pegol are captured by the QALY calculation, such as the effect the drug has on workplace and household productivity. However the committee considered that it had not been presented with any evidence to show an additional benefit over and above that already captured in the QALY. It concluded that all relevant benefits and costs were adequately captured by the QALY calculation.

# Pharmaceutical price regulations scheme (PPRS) 2014
The committee was aware of NICE's position statement on the Pharmaceutical Price Regulation Scheme (PPRS) 2014, and in particular the PPRS payment mechanism. It accepted the conclusion 'that the 2014 PPRS payment mechanism should not, as a matter of course, be regarded as a relevant consideration in its assessment of the cost effectiveness of branded medicines'. The committee heard nothing to suggest that there is any basis for taking a different view about the relevance of the PPRS to this appraisal. It therefore concluded that the PPRS payment mechanism was not relevant in considering the cost effectiveness of the technology in this appraisal.
TA415
Appraisal title: Certolizumab pegol for treating rheumatoid arthritis after inadequate response to a TNF Inhibitor
Section
Key conclusion
The committee considered that the incremental cost-effectiveness ratios (ICERs) showed that certolizumab pegol, in combination with methotrexate, is a cost-effective option for treating active rheumatoid arthritis in adults who have had an inadequate response to, or who cannot tolerate, other disease-modifying antirheumatic drugs (DMARDs), including at least 1 tumour necrosis factoralpha (TNFalpha) inhibitor, only if: disease activity is severe and the person cannot have rituximab therapy because rituximab is contraindicated or not tolerated and the company provides certolizumab pegol with the agreed patient access scheme.
The committee considered the ICERs showed that certolizumab pegol, as monotherapy, is a cost-effective option for treating active rheumatoid arthritis in adults whose disease has responded inadequately to, or who cannot tolerate, other DMARDs including at least 1 TNFalpha inhibitor, only if: disease activity is severe and rituximab therapy cannot be given because methotrexate is contraindicated or not tolerated and the company provides certolizumab pegol with the agreed patient access scheme.
The committee concluded that the ICERs showed that certolizumab, in combination with methotrexate, was not a cost-effective option for treating active rheumatoid arthritis in adults whose disease has responded inadequately to, or who cannot tolerate, other DMARDs including at least 1 TNFalpha inhibitor when disease activity is severe and when rituximab therapy can be considered a treatment option.
Current practice
Clinical need of patients, including the availability of alternative treatments
The committee heard from the clinical and patient expert that response to treatment is difficult to predict because patients' responses differ to biological DMARDs. The clinical expert expressed that a range of additional options of bDMARDs is valued at the positions in the pathway within existing NICE guidance. It is especially useful to have a range of bDMARDs when rituximab plus methotrexate cannot be considered due to adverse events related with rituximab.
The technology
Proposed benefits of the technology
How innovative is the technology in its potential to make a significant and substantial impact on health-related benefits?
The committee did not consider any claims about innovation that suggested there are additional innovative benefits that have not already been captured in the estimate of the quality-adjusted life year (QALY).
What is the position of the treatment in the pathway of care for the condition?
People whose disease has responded inadequately to treatment with a TNFalpha inhibitor. This is at the same point as the existing NICE technology appraisal guidance on adalimumab, etanercept, infliximab, rituximab and abatacept for the treatment of rheumatoid arthritis after the failure of a TNF-alpha inhibitor, golimumab for rheumatoid arthritis, and tocilizumab for rheumatoid arthritis.
Adverse reactions
No specific committee considerations.
Evidence for clinical effectiveness
Availability, nature and quality of evidence
The committee understood that the trials only showed a comparison of certolizumab pegol with placebo and accepted it was clinically effective over placebo. The committee understood that there were no trials comparing certolizumab pegol with comparator bDMARDs and that only mixed treatment comparisons were available.
Relevance to general clinical practice in the NHS
There were no direct head-to-head trials with treatments currently used in the NHS.
Uncertainties generated by the evidence
The committee was aware of uncertainties in the estimates from the meta-analyses methods used and it could not reliably conclude whether certolizumab pegol was more clinically effective than the comparator bDMARDs on the basis of the mixed treatment comparisons presented by the company.
Are there any clinically relevant subgroups for which there is evidence of differential effectiveness?
No specific committee considerations.
Estimate of the size of the clinical effectiveness including strength of supporting evidence
The committee noted that the effect size estimates from the company's mixed treatment comparison, comparing certolizumab pegol with comparator bDMARDs, were uncertain and concluded from the clinical expert's view that there was similar efficacy among the bDMARDs.
Evidence for cost effectiveness
Availability and nature of evidence
The company presented analyses of 3 distinct populations and a series of treatment sequences for people who have received a prior TNFalpha inhibitor. For people for whom rituximab is a treatment option, the committee agreed with the company that placing certolizumab pegol plus methotrexate after rituximab plus methotrexate was not a relevant comparator but noted that this was also true when placing certolizumab pegol plus methotrexate before rituximab plus methotrexate.
Uncertainties around and plausibility of assumptions and inputs in the economic model
The committee noted that the evidence review group's (ERG's) scenario analysis applied an assumption of equal efficacy among some of the bDMARDs. This resulted in the ICERs being dominated (that is, certolizumab pegol was more expensive but just as effective as the comparator bDMARDs), for the population for whom rituximab plus methotrexate is contraindicated or not tolerated and for whom methotrexate is contraindicated or not tolerated. The committee noted the similarities in costs and its conclusions on comparative efficacy, so that equivalence among bDMARDs could be accepted.
The committee heard that the company compared a longer intervention sequence that included another 6 treatments, with a comparator sequence without the intervention. It was aware that differential sequence lengths can exacerbate modelling uncertainties and, as such, skews the results in favour of the intervention. After consultation, the committee expressed uncertainties about the assumptions used in the company's model and preferred the ERG's values for the retreatment interval for rituximab and treatment durations (for TNFalpha inhibitors and nonTNFalpha inhibitors) from the REFLEX study and the extension to this study.
Incorporation of health-related quality-of-life benefits and utility values
Have any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered?
No other health-related benefits have been identified that have not been captured in the QALY calculation.
Are there specific groups of people for whom the technology is particularly cost effective?
No specific committee consideration.
What are the key drivers of cost effectiveness?
For people for whom rituximab is a treatment option, the committee looked at the elongated sequences used by the company in the analysis when certolizumab pegol plus methotrexate was placed before rituximab plus methotrexate. After consultation, the committee acknowledged that key drivers when certolizumab pegol plus methotrexate was used instead of rituximab plus methotrexate, were the retreatment interval for rituximab and the treatment durations for nonTNFalpha inhibitors and TNFalpha inhibitors. It concluded that a retreatment interval of 10.09 months, from the REFLEX study, was more plausible than that of 6.00 months used by the company. It also concluded that the original retreatment durations from NICE technology appraisal guidance on adalimumab, etanercept, infliximab, rituximab and abatacept for the treatment of rheumatoid arthritis after the failure of a TNF inhibitor were more plausible than an equal duration used by the company.
The committee noted the comparative efficacy assumptions placed on bDMARDs in the analysis for people for whom methotrexate is contraindicated or not tolerated. In the ERG's scenario analysis, this resulted in ICERs that were dominated for certolizumab pegol.
Most likely cost-effectiveness estimate (given as an ICER)
The committee concluded from the ERG scenario analyses that there was little difference in costs between comparator bDMARDs and certolizumab pegol so that equivalence among bDMARDs can be accepted for people for whom rituximab is contraindicated or not tolerated, and for people for whom methotrexate is contraindicated or not tolerated.
The committee concluded that the most likely ICER for people for whom rituximab plus methotrexate is a treatment option was above the normal range that would be considered a cost-effective use of NHS resources. The intervention was still dominated when the confidential patient access scheme for tocilizumab was taken into account.
Additional factors taken into account
Patient access schemes (PPRS)
Patient access schemes were taken into account for certolizumab pegol, golimumab, tocilizumab and abatacept.
End-of-life considerations
Not applicable.
Equalities considerations and social value judgements
The committee heard that certolizumab pegol may be beneficial in treating rheumatoid arthritis in pregnant women but acknowledged this use was outside the marketing authorisation. Because the committee makes recommendations within the marketing authorisation, it could not consider certolizumab pegol for use in pregnancy in its final recommendations. The committee concluded that it did not need to change its recommendations.