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The expected costs and QALYs of the alternative anti-TNFs are estimated and cost-effectiveness assessed based on the incremental cost per additional QALY gained. As an assumption is made concerning the similarity in terms of clinical effect between the alternative anti-TNFs, the differences between each of the treatments are driven entirely by their respective acquisition, administration and monitoring costs. Under this assumption, inevitably the lowest cost TNF-αinhibitor would clearly dominate (i.e. lower cost and equal effect) in a fully incremental comparison of cost-effectiveness. Consequently, each TNF-αinhibitor is compared separately versus CC alone. This provides a more consistent basis for assessing the impact that the different drug costs have across each separate scenario.

Probabilistic sensitivity analysis is used to assess the implications of parameter uncertainty (the imprecision with which input parameters are estimated). The mean costs and QALY reported in the tables are derived from the PSA and the probabilities that each TNF-αinhibitor is more cost-effective than CC alone are reported at thresholds of £20,000 and £30,000 per QALY.

Sensitivity analyses

A number of separate scenarios are presented to assess the implications of key parameter assumptions and sources of structural uncertainty in the model. These include the following.

Scenario 1: no response to conventional care assumed at 12 weeks

The base-case model incorporates the probability of response to CC at 12 weeks and assigns separate baselines to responders and non-responders. Although the changes in BASDAI/BASFI estimated at 12 weeks for CC are assumed to disappear in the following 12-week cycle, the separate baselines estimated for responders and non-responders are retained for the remainder of the model horizon. Given uncertainties surrounding the nature of the‘placebo’response assumed to apply to CC and whether or not this would be evident in actual clinical practice, a separate scenario was modelled which assumed that no patients receiving CC would achieve a BASDAI 50 response. This scenario was based on a separate simulation using the extended synthesis model where the magnitude of‘placebo’effect was assumed to be 0. Hence, employing this scenario, the impact of the‘placebo’effect is effectively netted out of the model for both CC and the anti-TNFs. Hence, although the difference in response rates and BASDAI/BASFI scores for responders to anti-TNFs remains similar to the base-case model, the absolute response rate for anti-TNFs and the absolute BASDAI/BASFI scores are lower when the adjustment is applied. In addition, as no response is assumed for CC, a single baseline BASDAI and BASFI score is applied to CC patients.

Scenario 2: different baselines assumed for responders and non-responders

In the base-case analysis, the extended synthesis model is used to estimate both changes in BASDAI and BASFI conditional upon BASDAI 50 response as well as different baseline BASDAI/BASFI scores for

responder and non-responders. It was noted inChapter 5that there appeared a disparity in the magnitude of the difference in the conditional baseline scores estimated from the extended synthesis model compared with the differences reported by those manufacturers who provided additional data on request.

Specifically, the difference between responders and non-responders appeared higher in our extended synthesis compared with the direct data reported by manufacturers. To explore the potential impact of this difference on the cost-effectiveness results, a separate scenario was undertaken wherein the difference in the conditional baselines was based on a pooled estimate of the differences across the trials provided by manufacturers rather than those estimated by the extended synthesis model.

In addition to exploring the impact of assuming different baselines, this scenario also included a pooled estimate of the change in BASDAI/BASFI scores for responders and non-responders reported by

manufacturers. Hence, in this scenario, the extended synthesis model is used only to predict the response to BASDAI 50, the differences in the conditional baselines and change scores being derived from pooled estimates from the data reported by manufacturers.

Scenario 3: no effect of anti-tumour necrosis factors on Bath Ankylosing Spondylitis Functional Index progression

In the base-case model, a treatment effect is applied from year 4 of the model on the rate of further BASFI progression for patients who continue to receive TNF-αinhibitors beyond this time point. Given the uncertainty reported inChapter 3surrounding existing evidence for anti-TNFs in relation to disease modification, a separate scenario was explored which assumed that the rate of BASFI progression would be the same for patients receiving anti-TNFs and CC alone.

Scenario 4: treatment effect of anti-tumour necrosis factors applied from start of model (Bath Ankylosing Spondylitis Functional Index progression)

A separate scenario was also undertaken assuming that the treatment effect on further BASFI progression would be incurred from the start of the model, as opposed to year 4. This scenario assumes that any disease modification would be achieved immediately compared with the delayed effect assumed in the base case.

Scenario 5: utilities–linear Bath Ankylosing Spondylitis Disease Activity

Index/Bath Ankylosing Spondylitis Functional Index model

The base-case analysis in both the AS and nr-AxSpA populations are based on the non-linear mapping algorithms reported in the submission by Pfizer. A separate scenario was run in both populations using an alternative linear model which has been applied in previous NICE appraisals (referred to as the‘Merck Sharp & Dohme’algorithm inHealth-related quality of life). This scenario was incorporated to explore the impact of using a linear model and to provide results which are more consistent with the utility approach applied in previous NICE appraisals (TA14317_{and TA233}33_).

Scenario 6 (non-radiographic axial spondyloarthritis only): trials in non-radiographic axial spondyloarthritis and ankylosing spondylitis populations combined

The base-case analysis for the nr-AxSpA population is based on the extended synthesis model using only the trials reporting in this population. A separate scenario was undertaken based on the results from the extended synthesis model which combined the AS and nr-AxSpA trials.

Following the consultation process to the NICE appraisal, additional analyses were undertaken to address comments received onChapters 5and6. These focused on the conditional baseline BASDAI scores used in Chapter 5and on the existence of a biosimilar product for infliximab with a lower list price. Further details on these analyses and their results are shown inAppendix 15.

Model validation

The conceptualisation of the model and related structural assumptions were informed by the review of existing models and discussions with two clinical advisors. The face validity of the model structure, data sources and key assumptions were addressed using inputs based on systematic reviews, targeted searching and clinical input. Verification of the model and the associated inputs was undertaken using a staged process. One researcher developed the initial model structure and the preliminary coding. This was then checked and extended for the final model by a second researcher. Both researchers were subsequently involved in the subsequent quality-assurance process entailing detailed cross-checks of input data against their sources and undertook extensive logical checks and scenarios to assess the performance of the model. Two other researchers were involved in further checks of key aspects including the integration of the results from the extended synthesis within the Excel model. A fifth researcher was involved in all stages with preparing and checking parameter inputs for the model. Cross-validation was assessed by comparing the results with existing models and identifying differences and their causes.

Results of the independent economic assessment