Secukinumab for treating moderate to severe plaque psoriasis

Clinical effectiveness

4.4 The Committee considered the clinical trials identified in the company submission, agreeing that the company had included relevant, high‑quality trials which contained comparisons with both placebo and an active comparator. It concluded that the clinical trial evidence was appropriate for decision‑making.

4.5 The Committee considered the baseline characteristics of the patients in the trials and heard from clinical experts that they broadly reflected the UK population with severe psoriasis. The Committee noted that the population in the trials and the marketing authorisation for secukinumab included people who are candidates for 'systemic therapy', which is defined as including both non‑biological and biological treatments. Therefore, both the trials and marketing authorisation included some patients who had never received systemic or biological treatments, whereas the scope for this appraisal was narrower ('people for whom systemic treatments are not tolerated, not effective or contraindicated'). The clinical experts agreed with the company that, in clinical practice, secukinumab would be offered at the same time as the existing biological treatments rather than before. Because the results of the trials reflected the effectiveness of secukinumab in a population including people who had not previously received systemic treatments, the Committee was concerned about the extent to which prior systemic treatment could impact the clinical‑effectiveness results of secukinumab. It heard from clinical experts that they did not expect prior systemic treatments to modify the effectiveness of secukinumab. With respect to prior biological treatments, most of which are TNF‑alpha inhibitors, the clinical experts noted that, because secukinumab has a different mechanism of action, they did not expect a change in effectiveness; in general, they were not aware of any evidence that prior treatment impacts the clinical effectiveness of current treatment. However, the Committee concluded that that it would have been more appropriate to present the results of an analysis excluding patients who had never received systemic therapies in line with the population in for which it was proposed to be used. Overall, the Committee concluded that, although the populations in the scope and trial differed, the results of the clinical trials were likely to be generalisable to patients with severe psoriasis and were appropriate for decision‑making on the clinical effectiveness of secukinumab.

4.6 The Committee considered the relevance of the main outcomes used in the trials (that is, percentage reduction in PASI score), to clinical practice. The Committee debated whether measuring an improvement in PASI was objective; it heard from the clinical experts that, once experienced, clinicians can do a PASI assessment quickly with little variability between clinicians. For PASI 75, the primary outcome in the trials, the Committee agreed that this demonstrated whether treatments for psoriasis had a high level of effectiveness. However, even with outcomes such as PASI 75, the psoriasis that remains could still have a significant impact on quality of life, and therefore patients value any treatment that could completely clear the disease (that is, PASI 100). The Committee concluded that PASI 75 was a clinically relevant definition of response to treatment and that, in addition, complete clearance was important; therefore the evidence for PASI 100 should be taken into account when deciding the value of secukinumab to the NHS.

4.7 The Committee discussed the results of the clinical trials. It noted that the clinical trial evidence for secukinumab had generated statistically significant differences in the co‑primary outcomes when compared with both placebo and etanercept (an active comparator that is already recommended by NICE for the population covered by this appraisal). It further noted that a PASI 100 response (that is, complete clearance of disease), occurred more often with secukinumab than with either placebo or etanercept, and that complete clearance of disease was the most important outcome for patients (see sections 4.2 and 4.6). The Committee heard from the clinical experts that the effectiveness of secukinumab and other biologicals is likely to be lower in clinical practice than in the trials, in part, because trials may not include patients with refractory disease. The clinical experts considered treatment with secukinumab to represent a step‑change in the management of psoriasis because it appears to clear disease in some patients, offers a different mechanism of action compared with the TNF‑alpha inhibitors and ustekinumab, and is associated with a low risk of adverse events. The Committee concluded that the evidence had shown that secukinumab was clinically superior to both placebo and etanercept for all primary and secondary outcomes.

4.8 The Committee considered the network meta‑analysis presented by the company to compare secukinumab with the other biological agents specified in the scope. The Committee considered potential limitations of the network meta‑analysis which did not address possible heterogeneity of the patients involved in the trials (for example, prior treatments received). However, it noted that the secukinumab trial populations were likely to be similar with respect to heterogeneity to the trials to which they were being compared, and which formed the basis for previous NICE guidance. The Committee noted that the difference in effectiveness between secukinumab and etanercept was smaller in the direct trial evidence than it was in the network meta‑analysis, which the company used for its modelling (see section 3.6 and table 3). The Committee further noted that, although the results of the network meta‑analysis suggested that secukinumab appears to be more clinically effective than etanercept and adalimumab, and to have similar clinical effectiveness to ustekinumab and infliximab, the only direct trial evidence was for secukinumab compared with etanercept. Therefore the Committee considered that the relative clinical effectiveness of biological treatments for all outcomes was unknown. The Committee was also concerned about the effectiveness of best supportive care generated by the network meta‑analysis reflected, which appeared very low with only 3.6% of people randomised to best supportive care having a PASI 75 response. It heard from clinicians that, in clinical practice, the proportion of people with a PASI 75 response following treatment with best supportive care was likely to be substantially higher (possibly up to 60%) because best supportive care involves active treatments such as topical therapies, ciclosporin and phototherapy. However, the clinical experts stated that a response with best supportive care would be accompanied by disutility because of the intensive, time‑consuming, inconvenient and unpleasant treatments, and with patients relapsing sooner than with biologicals. Overall, the Committee agreed that there were a number of scenarios it would like to have seen presented in the company submission, including a network meta‑analysis for additional outcomes such as utility values, and the impact of prior treatment, to help provide additional assurances about the robustness of the efficacy assumptions. However, it concluded that, despite the limitations of the network meta‑analysis, it was sufficient for the purposes of decision‑making.

4.9 The Committee discussed whether there were any relevant subgroups in which secukinumab might be more effective than in the overall population included in the trials, or which have more to gain. The Committee reflected that it would have liked to have seen more analyses using patient‑level data for people who have previously received either systemic non‑biological or biological treatments, to help reduce any uncertainty about the extent to which prior treatment affects clinical effectiveness. The Committee further heard from the clinical experts that people with concomitant psoriatic arthritis were an important subgroup, particularly those with psoriatic arthritis affecting joints of the hand which could cause difficulty with self‑injecting. The Committee was aware that the monthly administration of secukinumab would be easier to manage for these patients than of other biological agents that need to be injected more frequently. The Committee noted that the company was applying for a marketing authorisation for secukinumab for psoriatic arthritis, that this was being considered for appraisal by NICE, and that ideally 1 treatment would be given for both conditions. In addition, the Committee was aware that there may be small subgroups of patients with comorbidities in whom TNF‑alpha inhibitors would be contraindicated or used with caution (such as people with demyelinating diseases or heart failure) and for whom treatment with secukinumab would be preferred. The Committee discussed whether observational data exists, and learned of a UK registry for biologicals; the company informed the Committee that it did not have access to this registry. The Committee concluded that future appraisals would benefit from UK observational data, but at present there were not sufficient data to identify differential efficacy between people who had received different prior treatments.

4.10 The Committee discussed the adverse events associated with secukinumab, noting that it was generally tolerated, and that the events were consistent between the placebo, etanercept, and secukinumab 300 mg and 150 mg arms of the trials. The Committee was aware that, over time, real‑world data on adverse events will accumulate. Given the evidence to date, the Committee concluded that secukinumab did not appear to be associated with adverse events not already known for biological treatments in general.

Cost effectiveness

4.11 The Committee considered the company's health economic model and noted that the structure of the model was similar to previous appraisals for psoriasis, but did not represent established clinical practice for managing severe psoriasis in several ways including:

4.12 The Committee considered the sources used by the company to estimate resource use and costs associated with best supportive care, noting that the model was highly sensitive to these inputs, and specifically whether assumptions were taken from Fonia et al. (2010; the Evidence Review Group [(ERG] base case) or NICE's psoriasis guideline and hospital episode statistics (HES) data (the company base case). The Committee noted that, in both instances, the resource use estimates of best supportive care were likely to overestimate actual current best supportive care. This is in part because the populations described in Fonia et al. and the costing template for NICE's psoriasis guideline differed from the population in this appraisal; the costing template for NICE's psoriasis guideline was for a specific, high‑need subpopulation with very severe psoriasis, and Fonia et al. describes care in a tertiary care centre known for treating the most severely affected patients. The Committee further noted that HES data (used to inform length of stay in the base case) were not specifically only for people receiving treatment for psoriasis nor did they necessarily show the number of individual patients who were admitted. The Committee also heard from the clinical experts that, in recent years, the number of patients hospitalised for severe psoriasis has fallen (see section 4.2) because of the availability of a wider range of biological treatment options; therefore, overall hospitalisation costs associated with psoriasis have fallen. The Committee considered that neither the resource use from Fonia et al. nor from NICE's psoriasis guideline and HES data were plausible for the population with severe psoriasis. However, it concluded that resource use for best supportive care is closer to Fonia et al. than to the company's estimates, and that future appraisals for psoriasis should take into account the changes in relevant costs that have occurred over time. The Committee further concluded that defining costs associated with psoriasis was an area of high priority for research.

4.13 The Committee considered the assumption in the company's model that people who receive subcutaneous biological treatments are able to self‑administer treatments after 1 hour of training. It noted that the ERG considered this unrealistic because a proportion of people would not be able to self‑administer treatment (for example, because of physical disability or needle‑phobia), and that a more realistic training time estimate would be closer to 3 hours. It heard from clinical experts that most people would be competent at self‑administration after 2 hours of training. However, most training sessions would take place during normal clinical visits, and so self‑administration training was a cost that did not necessarily need to be separately modelled. Further, the clinical experts stated that the proportion unable to self‑administer treatments subcutaneously would be small. The Committee noted that the ERG base cases included 3 hours of training rather than 1 hour, and the company was happy with this change, which did not have a large impact on cost‑effectiveness estimates. The Committee concluded that it was clinically plausible to assume that most people could self‑administer subcutaneous biological treatments, and that it was appropriate to model training costs using a time of 1–3 hours.

4.14 The Committee considered the company's assumption that modelled patients after treatment during the induction period remain in the same health state for the duration of treatment. It noted clinical data from the FIXTURE trial that showed that some people who were in the PASI 50–74 health state at 12 weeks got better, while others got worse over the remaining 52‑week time period of the model. However the Committee heard from clinical experts that, in clinical practice, with some exceptions, the health state of most people with psoriasis generally remained stable after the induction period. This reassured the Committee that it was reasonable to assume in the model that people remain in the same heath state.

4.15 The Committee discussed the validity of the clinical‑effectiveness data from the network meta‑analysis used by the company in its model. It was aware that registry data exist in the UK, but were not provided in the company's submission because the company stated it did not have access to the data. The Committee agreed that these registry data were a rich source of information about the treatment of people with psoriasis and was disappointed that the company did not have access to these data. The Committee was concerned about the implausibly low value of 3.6% for the proportion of patients whose disease responds to best supportive care treatment (see section 4.8). The Committee noted that the population generating the clinical data underpinning the model had an average PASI higher than 20, which it understood reflected very severe psoriasis, therefore the response rates from the trials may be more relevant for people with very severe disease. The Committee concluded that, in the absence of 'real life' data on the response rates for secukinumab compared with other treatments, the network meta‑analysis assumptions were appropriate to use. However, it concluded that the issues with the network meta‑analysis added to the uncertainty in the cost‑effectiveness estimates generated by the model.

4.16 The Committee considered the company's modelling assumption that 20% of all patients stop biological treatments each year, an assumption the company based on previous appraisals. The Committee heard from clinical experts that this rate was likely to be an overestimate because clinicians had an increasing number of treatments from which to choose. The Committee concluded that fewer patients stopped biologicals than had been assumed by the company but that, because this affected all biological treatments equally, this was likely to have a minimal effect on the cost effectiveness of secukinumab.

4.17 The Committee considered the quality of life and utility values used by the company in its model. It welcomed the use of utility values from trial data (in accordance with the guide to the methods of technology appraisals). However, it noted that the company had used a regression analysis (taking into account PASI and DLQI scores) to predict the utility values in the model. The Committee agreed it that would have preferred to have seen the unadjusted EQ‑5D utility values used in the model. The Committee discussed the plausibility of the absolute values used by the company, agreeing that the baseline utility value (0.642) seemed plausible, although the quality‑adjusted life year (QALY) gain with biological treatments appeared to be low. The Committee noted this may have been because the model did not assume a survival benefit associated with treatment. The Committee noted that the model did not take into account the disutility values associated with best supportive care, and the added benefit of obtaining a complete remission with secukinumab (PASI 100), an important outcome for patients. The Committee concluded that the utility gains estimated from the model were likely to be underestimated.

4.18 The Committee discussed whether secukinumab could be considered innovative. It noted that secukinumab offers a different mechanism of action to the other biological treatments recommended by NICE, and some patients experience complete clearance of disease. The Committee also heard from clinical and patient experts that severe psoriasis can be associated with a stigma apart from its effect on health‑related quality of life, and that NICE methods acknowledge giving extra weight to such conditions. Further, the Committee noted that the disutility of best supportive care was not included in the model. The Committee agreed that these benefits had not been captured when calculating the QALY, that secukinumab reflected a step change in treatment and that the drug could be considered innovative.

4.19 The Committee discussed the estimate of cost effectiveness based on the incremental analyses presented by the company. It noted that the ICERs were sensitive to the costs of best supportive care and the cost of secukinumab, and less sensitive to utility values or assumed rates of stopping biological treatment. However, the Committee considered there to be significant structural and parameter uncertainties in the way that the treatment of psoriasis had been modelled, including: the short time horizon; the assumption that people receive only 1 treatment before best supportive care; and the low effectiveness of best supportive care. It further noted that, because the changes in incremental health benefits between different biological treatments were small, the ICERs could vary dramatically with small QALY changes. The Committee concluded that these structural and parameter uncertainties and the labile nature of the ICERs made it difficult to determine a precise cost‑effectiveness estimate.

4.20 The Committee discussed whether it could determine a most plausible ICER, but agreed this was difficult because of the previously mentioned structural and parameter uncertainties in the model. The Committee and the company both agreed with the ERG's corrections to the model. The Committee also agreed that the most plausible assumptions on resource use were closer to Fonia et al. (2010; ERG base case) than to NICE's psoriasis guideline (company base case). Furthermore, the Committee considered that the ICERs compared with the biological treatments rather than with best supportive care were most appropriate. It agreed that the ICERs ranging from approximately £17,700 per QALY gained (compared with ustekinumab 90 mg) to £42,400 per QALY gained (compared with etanercept) were probably overestimated because the model had not accounted for PASI 100 responses (see section 4.17) nor the disutility values associated with best supportive care. In addition, the Committee pragmatically considered the cost effectiveness of secukinumab in the light of previous appraisals in this disease area. The Committee noted that, even when using direct trial data, secukinumab was more effective than at least one of the already recommended biologicals, etanercept, and was associated with a higher probability of complete remission. Considering the patient access scheme price of secukinumab, the clinical data (compared with etanercept in the FIXTURE trial and with the results of the network meta‑analysis), and the testimony of the experts, the Committee concluded that the most plausible ICER was likely to be in line with the other biologicals already recommended in previous NICE guidance. The Committee therefore concluded that secukinumab could be recommended as a cost‑effective use of NHS resources.

4.21 The Committee discussed the inclusion of a stopping rule in the recommendation. When discussing the appropriate time point at which to measure response, it noted that the trials and the model assessed the effectiveness of secukinumab for the primary outcome at week 12. The Committee was aware that because the clinical effectiveness of secukinumab continued beyond 12 weeks (with a peak effect at week 16), the summary of product characteristics notes that consideration should be given to stopping treatment in people who have not shown a response up to week 16. However, the Committee noted that there is no appropriate placebo data with which to compare the clinical effectiveness of secukinumab at 16 weeks because patients in the placebo arm of the trials were able to crossover to active treatment if they did not have a response at week 12. Also, the company base case used a 12‑week stopping rule. The Committee considered the relevance of stopping rules in existing NICE guidance for biologicals for treating severe psoriasis that, in addition to the PASI 75 response, also refers to a PASI 50 response with a 5‑point reduction in DLQI from the start of treatment. The Committee considered that, because secukinumab was likely to be given at the same point in the pathway as the other biologicals already recommended by NICE for treating psoriasis, any stopping rules should be consistent with previous appraisals. The Committee concluded that the most appropriate time point to assess response was week 12, and that the outcomes used to assess response should be consistent with previous appraisals for psoriasis.

4.22 The Committee was aware that there might be some situations when the DLQI may not be a clinically appropriate tool to inform a clinician's conclusion about the severity of psoriasis; for example, if a person has physical, sensory or learning disabilities, or communication difficulties that could affect their responses to the questionnaire. The Committee heard from the clinical specialists that the DLQI is now available in more than 50 languages and that this has improved assessment for those people whose first language is not English. The Committee concluded that healthcare professionals should take any physical, sensory or learning disabilities and communication difficulties into account when using the DLQI and make any adjustments they consider appropriate.

4.23 The Committee considered a potential equality issue raised by a patient organisation that people with psoriatic arthritis affecting their fingers could find using the pre‑filled syringe difficult, as could those with a needle phobia. The Committee had already concluded that the monthly administration of secukinumab would be easier to manage for these patients than of other biological agents that need to be injected more frequently (see section 4.9). Bearing in mind that the Committee had recommended secukinumab (see section 4.20), it concluded that there was no need to alter or add to its recommendations. It also noted that a separate appraisal was being considered for secukinumab for people with psoriatic arthritis.

4.24 The Appraisal Committee considered whether it should take into account the consequences of the Pharmaceutical Price Regulation Scheme (PPRS) 2014, and in particular the PPRS Payment Mechanism, when appraising secukinumab. The Appraisal Committee noted NICE's position statement in this regard, and 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 with regard to the relevance of the PPRS to this appraisal of secukinumab. It therefore concluded that the PPRS Payment Mechanism was irrelevant for the consideration of cost effectiveness of secukinumab.

Summary of Appraisal Committee's key conclusions