Ciclosporin for treating dry eye disease that has not improved despite treatment with artificial tears

Clinical effectiveness

3.1 The company identified 2 multicentre (including the UK) double‑masked, randomised controlled clinical trials relevant to the decision problem, SANSIKA and SICCANOVE. These trials compared ciclosporin with a vehicle in people with dry eye disease that had not improved despite treatment with artificial tears. The company presented results from both SANSIKA and SICCANOVE but considered SANSIKA to be most relevant to the decision problem, because it included only people with severe dry eye disease (whereas SICCANOVE included people with moderate to severe dry eye disease). Only details and results of SANSIKA are presented here.

3.2 SANSIKA (n=246) included patients with severe keratitis and severe dry eye disease defined as having a Corneal Fluorescein Score (CFS) of 4 on the modified Oxford scale, a Schirmer score (without anaesthesia) of 2 mm to 10 mm and an Ocular Surface Disease Index (OSDI) score of 23 or more. The trial compared ciclosporin in combination with artificial tears with the vehicle plus artificial tears. The vehicle contained the excipient cetalkonium chloride and patients were allowed to use preservative‑free artificial tears as needed. SANSIKA was divided into 2 parts: part 1 studied the efficacy of ciclosporin over 6 months (n=245) and part 2, a 24‑week open‑label extension, assessed the long‑term safety of ciclosporin up to 12 months (n=207). Randomisation was stratified by centre. Treatment compliance was measured by the number of used and unused containers of ciclosporin in relation to the duration of the follow-up interval.

3.3 The primary end point was change from baseline in CFS‑OSDI, a composite variable combining the CFS and OSDI scores, at month 6. The definition of response using CFS‑OSDI was:

3.4 The efficacy end points were analysed based on the full analysis set (n=245 in SANSIKA part 1 and n=207 in SANSIKA part 2), which included all patients who had any amount of study drug and for whom post‑baseline data were available. Statistical significance was set at a significance level of 5% (p≤0.05). The analyses for the safety end points were based on the safety analysis set (n=244 in SANSIKA part 1 and n=207 in SANSIKA part 2), which included all patients for whom there was evidence that they used the study medication. The company carried out several post hoc subgroup analyses including of the primary efficacy end point CFS‑ODSI response rate (setting CFS improvement at 3 grades instead of 2).

3.5 The company presented the results from SANSIKA for the primary end point and noted that none of the results presented was statistically significant. The company stated that there are many possible explanations for this, including the lack of correlation between signs and symptoms of dry eye disease and the possible beneficial effects of the vehicle itself.

3.6 The company presented an analysis of CFS score change from baseline over time in SANSIKA, which showed a statistically significant decrease in both treatment groups (p<0.001). It noted that there was a statistically significant benefit with ciclosporin compared with the vehicle over the 6‑month treatment period (p=0.017). At 6 months, the decrease in CFS score from baseline was statistically significantly greater with ciclosporin than with the vehicle (p=0.037).

3.7 From its post hoc analysis of CSF‑OSDI in SANSIKA (using an improvement of 3 grades or more in CSF as criteria for improvement), the company noted that there was a statistically significantly higher response with ciclosporin (imputed data: 18.8%; observed data: 21.4%) compared with the vehicle (imputed data: 7.7%; observed data: 8.5%; p=0.016 and p=0.012 based on imputed and observed data respectively).

3.8 Results of HLA‑DR in SANSIKA showed that at 6 months, ciclosporin was associated with a statistically significant decrease in HLA‑DR from baseline compared with the vehicle (p=0.021). This demonstrated that ciclosporin had an anti‑inflammatory effect. The company noted that this is important because dry eye disease is characterised by inflammatory changes on the ocular surface.

3.9 The company presented the median use of artificial tears instead of the mean because the data distribution was skewed. It stated that there were no differences in the use of artificial tears between treatment groups during all visits in part 1 in SANSIKA but noted that the number of missing data was high. The company stated that considering all available data, there was a progressive decrease in the use of artificial tears over time in both treatment groups. The results in part 2 showed a steady decrease in the use of artificial tears during the first 6 months in both treatment groups (−3.8 drops per day per eye in people who had ciclosporin in both parts of SANSIKA, and −2.6 drops per day per eye in people who had the vehicle alone in part 1 and ciclosporin in part 2).

3.10 The company also analysed CFS‑OSDI response rates in part 2 of SANSIKA. It noted that responses were similar in both treatment groups at months 9 and 12. At month 12, for people who had ciclosporin in both parts of SANSIKA, the response rate was 39.1%; for those who had the vehicle alone in part 1 and switched to ciclosporin in part 2, the response rate was 38.0%.

3.11 The company presented the health‑related quality of life results from SANSIKA using the NEI‑VFQ‑25 and EQ‑5D questionnaires. The results using NEI‑VFQ‑25 were similar between treatment groups at baseline and at 6 months but there was an increase in the mean NEI‑VFQ‑25 composite score over time in both treatment groups. There were no differences in the EQ‑5D summary index and the EQ‑5D VAS score between baseline and at 6 months in both treatment groups, or between treatment groups. The company noted that the tariff used to estimate the health utility values was based on UK data from 1993 (Rabin et al. 2011).

3.12 The company presented the results of meta-analyses of SICCANOVE and SANSIKA for the composite end point CFS‑OSDI response rate at 6 months for:

3.13 The company presented pooled adverse effects results from SANSIKA and SICCANOVE. The company explained that treatment-emergent adverse effects represent any event occurring after the baseline visits, related or not to the study medication, whereas treatment‑related adverse effects represent an event considered by the investigator to be related to the study medication. The most frequent treatment‑emergent adverse effects with ciclosporin were instillation site pain, eye irritation, instillation site irritation and eye pain. The most frequent treatment‑emergent adverse effects with the vehicle were eye pain, meibomianitis (an inflammation of the meibomian glands, a group of sebaceous glands in the eyelids) and reduced visual acuity. The company concluded that the observed adverse effects of ciclosporin were mild to moderate and temporary and that overall ciclosporin is safe and well tolerated.

Cost effectiveness

3.14 The company presented a de novo Markov economic model that assessed the cost effectiveness of ciclosporin compared with standard care (artificial tears) in patients aged over 18 years with dry eye disease and severe keratitis whose disease had not adequately responded to artificial tears. The company stated that the cost‑effectiveness analysis was conducted from an NHS and Personal and Social Services perspective, costs and outcomes were discounted at 3.5% per year, the time horizon was 30 years and the cycle length was 3 months. The company noted that because patients in SANSIKA represent the licensed population, inputs in the model were derived from this trial where possible. Because the comparator in SANSIKA (vehicle, which contained the excipient cetalkonium chloride) is not commercially available and artificial tears represent established clinical practice in the NHS for this population, the company viewed the response or reduction in the use of artificial tears in the vehicle group as a regression to the mean. The baseline use of artificial tears in SANSIKA was assumed to be reflective of standard care in the NHS. The model included 7 different states: treatment induction, treatment responders, non‑responders, temporary punctal plugs, permanent punctal plugs, post plugs and death. Patients were assumed to be aged 61 years, they could die at any time, and the model included equal numbers of men and women.

3.15 Treatment response was represented using the observed data from the post hoc analysis of CFS‑OSDI response rate from part 1 of SANSIKA (defined as improvement of 3 points or more from baseline CFS and improvement of 30% or more from baseline OSDI). Response rates from the vehicle group were used to derive response rates for the artificial tears group in the model. People whose disease responded to the 6‑month induction period continued treatment until there was no response. These response rates were derived from part 2 of SANSIKA. Patients who had the vehicle in part 1 of SANSIKA and ciclosporin in part 2 were not included in the estimates for the model. The company assumed that transition probabilities were constant over time. The probability of stopping treatment with ciclosporin after 6 months (the end of SANSIKA) was taken from the rate of patients stopping treatment with ciclosporin between 6 and 12 months in part 2 of SANSIKA. For the artificial tears group, the rate of patients who stopped having the vehicle during part 1 of SANSIKA was used as a proxy for the estimates after the end of the trial. The annual rate of temporary punctal plugs was assumed to be 0.01 based on a study by Clegg (2006) and only 10% of people who had temporary punctal plugs were assumed to then have permanent punctal plugs. The response rate to permanent punctal plugs was assumed to be 100%. Patients with temporary or permanent punctal plugs were assumed to not use artificial tears. Mortality rates were derived from the general population aged 61 years, which was the mean age of patients in SANSIKA.

3.16 The composition of preservative‑free artificial tears was polyvinyl alcohol, carbomers and paraffin. The company assumed that administration, monitoring and testing costs with ciclosporin or artificial tears were zero, because all treatments were self‑administered and it was assumed that the rate of ophthalmologist visits, tests and monitoring were similar in both treatment groups irrespective of the response status of the disease. It was assumed that people with severe dry eye disease have treatment in both eyes. The company assumed that the average number of drops per eye per day at baseline was similar in both treatment groups as in SANSIKA. The company incorporated the change in artificial tear use at 6 months to the ciclosporin and artificial tears groups in SANSIKA in the model, noting that the vehicle could have had an effect on the reduction of artificial tears use in the comparator group. For patients whose disease did not respond to treatment, the number of artificial tears per eye per day was similar to this use at baseline. Because treatment‑related adverse effects were of low severity and transient, these were not included in the model other than through a reduction in the treatment continuation rates. The source of the costs for punctal plugs was NHS Reference Costs 2013. Unit costs were taken from the British National Formulary (month not stated).

3.17 The company used utility data from SANSIKA in the model (utility for response: 0.74; utility for no response: 0.66). It noted that patients whose disease responds need fewer artificial tears and have a higher utility, which was assumed to be constant during response. Patients with punctal plugs had the same utility as patients whose disease responds with ciclosporin or artificial tears.

3.18 The company's cost‑effectiveness analysis produced an incremental cost‑effectiveness ratio (ICER) for ciclosporin plus artificial tears compared with vehicle plus artificial tears of £19,156 per quality‑adjusted life year (QALY) gained, with an associated incremental cost of £713 and 0.037 additional QALYs.

3.19 The company conducted deterministic and probabilistic sensitivity analyses, which showed that varying the utility value for responders had the largest effect on the ICER. When varying the utility value for responders between 0.67 and 0.81, the ICER for ciclosporin plus artificial tears compared with artificial tears alone ranged from £165,654 to £10,166 per QALY gained. Other variables that had a notable effect on the ICER were the acquisition cost of ciclosporin and the response probabilities to ciclosporin and the vehicle at 6 months. The probabilistic analysis results gave an ICER of £18,835 per QALY gained for ciclosporin plus artificial tears compared with vehicle plus artificial tears. The company noted that ciclosporin had a probability of 46.4% to be considered a cost‑effective use of NHS resources at a maximum acceptable ICER of £20,000 per QALY gained. It also noted that a number of simulations were associated with incremental benefits close to zero, meaning that the probabilistic results should be interpreted with caution.

3.20 The company presented results from several scenario analyses including:

3.21 The company did not present a subgroup analysis for patients with Sjögren's syndrome. It noted that SANSIKA was not powered to assess the benefit of ciclosporin in this subgroup, and any inference would have meant using published literature in different patient groups or clinical input which would have added uncertainty to the model.

ERG comments

3.22 The ERG noted that only 17% of patients included in SICCANOVE had severe dry eye disease (as per the definition used in SANSIKA), and that the company presented post hoc analyses for them. The ERG considered that these post hoc analyses were appropriately used to inform pre‑specified analyses in SANSIKA and agreed with the company that evidence from SANSIKA is more relevant to the decision problem.

3.23 The ERG considered that the value of the evidence from SANSIKA is limited because the comparator is the ciclosporin vehicle, rather than any of the comparators specified in the NICE scope. The ERG noted that the vehicle on its own is not commercially available and it is not currently used in routine clinical practice. The ERG considered that the improvements seen in the comparator group in the trial may be because of the vehicle itself, concomitant use of artificial tears or both. The ERG considered that the relevant comparator for ciclosporin was actually other ciclosporin formulations currently used in clinical practice in England. However, the ERG noted that because there are no trials comparing ciclosporin with other pharmaceutical formulations, combined with the absence of a common comparator and the differences in vehicles used in each formulation, a robust indirect comparison was not possible.

3.24 The ERG commented on the clinical relevance of the composite primary end point in SANSIKA (CFS‑OSDI response defined as improvement of 2 points or more from baseline CFS and improvement of 30% or more from baseline in OSDI). It noted that both CFS and OSDI are recognised and validated outcomes to measure signs and symptoms respectively, but was concerned that the validity of the composite end point is unknown. The ERG stated that it is unclear whether CFS‑OSDI response is a clinically relevant end point and what the response thresholds should be to define a response. It also noted that the response thresholds would depend on the criteria used for defining severe dry eye disease.

3.25 The ERG noted that the pooled adverse effects data for SICCANOVE and SANSIKA presented by the company included an estimate for the relative risk between treatment groups, implying that statistical analyses were conducted. The ERG stated that although pooling adverse effects data is normally the preferred method for reporting the adverse effects results, only SANSIKA included patients with severe dry eye disease exclusively and different vehicles were used in SANSIKA and SICCANOVE. It therefore considered the results of SANSIKA to be of greater importance for the appraisal. The ERG also noted that there were some differences in the rates of adverse effects between SANSIKA and SICCANOVE, and considered that these differences may be because of the use of different vehicles or differences in disease severity between the 2 trials.

3.26 The ERG considered that results from SANSIKA could not be used directly to inform an economic evaluation because the comparator (vehicle) is not commercially available and is not currently used in routine clinical practice (which the ERG considered to be other ciclosporin formulations). However, because of the lack of data, it noted that the only valid economic comparison would be a cost‑minimisation analysis assuming that all ciclosporin‑based treatments have equivalent efficacy, similar adverse effects and similar administration, prescribing and monitoring costs. The ERG considered that there was no sufficient evidence available to support a cost‑effectiveness analysis of ciclosporin compared with established clinical practice in the NHS for severe dry eye disease. Although the ERG provided further critique on the company's economic model, it highlighted that this should not be understood as any expression of support for the validity of the model or the results obtained from it.

3.27 The ERG noted that there were more women (85.3%) than men in SANSIKA and that the age range at baseline was wide (22 to 87 years). The ERG considered that it would be more appropriate to carry out modelling for each age and gender group, combining the results to obtain a weighted average result. Having done this, the resulting ICER for ciclosporin plus artificial tears compared with vehicle plus artificial tears was £19,382 per QALY gained when using the post hoc CFS‑OSDI definition of response from SANSIKA, and £33,625 per QALY gained when using the trial CFS‑OSDI definition of response from SANSIKA.

3.28 The ERG noted that the company used the post hoc definition of CFS‑OSDI response from SANSIKA, which is more restrictive than the trial definition. It stated that this had a large effect on the cost‑effectiveness results because it excluded the level of benefit that most favoured the vehicle group.

3.29 The ERG highlighted the population heterogeneity in the company's model. It noted that approximately 10% of patients in SANSIKA were diagnosed less than 2 years before randomisation and that there was no statistically significant difference in CFS‑OSDI response from baseline at 6 months in the ciclosporin group using either the pre‑specified (p=0.41) or the post hoc (p=0.98) definition of response. However, it noted that patients who had vehicle and were diagnosed less than 2 years before randomisation showed CFS‑OSDI response rates nearly double those in patients having ciclosporin. The ERG cautioned that there were too few patients in this analysis to derive definite conclusions but suggested that patients who were more recently diagnosed may show short‑term improvements in their condition, delaying the need for treatments such as ciclosporin.

3.30 The ERG noted that the company applied probabilities for continuing treatment beyond the end of the trial from different time periods for each treatment group (6–12 months for ciclosporin and 0–6 months for the vehicle), indicating lower discontinuation rates in the ciclosporin group (10.9%) than in the vehicle group (12.2%). However, it also noted that Kaplan–Meier analyses in SANSIKA showed that there was a higher rate of stopping treatment in the ciclosporin group during the first month remaining stable thereafter (5.9% per 3 months) and that rates of stopping treatment were lower in the vehicle group with no evidence of any initial excess of people stopping treatment (4.6% per 3 months). The ERG applied these rates in scenario analyses and noted that this was its preferred option for modelling stopping treatment rates. The results increased the ICER of ciclosporin plus artificial tears compared with vehicle plus artificial tears to £25,020 per QALY gained when using the post hoc CSF‑OSDI definition of response, and to £133,290 per QALY gained when using the trial definition of response.

3.31 The ERG found an inconsistency between the company's calculation of artificial tear use at baseline and at 6 months. The ERG considered that no differences in artificial tear use between treatment groups should be included in the model at baseline and at 6 months because neither of these differences was statistically significant. The ERG applied an average use of 6.83 drops per eye per day to both treatment groups in the model in scenario analyses, which produced ICERs for ciclosporin plus artificial tears compared with vehicle plus artificial tears of £20,950 per QALY gained when using the post hoc CFS‑OSDI definition of response, and £36,307 per QALY gained when using the trial CFS‑OSDI definition of response.

3.32 The ERG also noted that the company applied treatment costs in the first 6 months assuming that treatment is prescribed for 3 months at the beginning of each cycle. It considered that this does not take into account the small risk of patients dying or stopping treatment during a 3‑month cycle. Based on clinical advice, the ERG assumed that treatment was prescribed monthly in its scenario analyses. These produced ICERs for ciclosporin plus artificial tears compared with vehicle plus artificial tears of £21,916 per QALY gained when using the post hoc CSF‑OSDI definition of response, and £35,915 per QALY gained when using the trial CFS‑OSDI definition of response.

3.33 The ERG noted that the company's approach to modelling the utility values based on response is not influenced by treatment because EQ‑5D results are pooled across both treatment groups. The ERG examined the EQ‑5D results and noted that patients in the vehicle group showed a larger utility benefit based on response compared with patients in the ciclosporin group (+0.038 using the trial definition of response, or +0.049 using the post hoc definition). The ERG stated that pooling utility values in the model by response eliminated the potential effect of any differences because of treatment. The ERG considered that the most likely reason for the observed differences in utility values between treatments was that the additional adverse effects in patients having ciclosporin reduced the advantages derived from a response to treatment. The ERG investigated the effect of using separate trial utility values for each treatment group in scenario analyses, and obtained an ICER for ciclosporin plus artificial tears compared with vehicle plus artificial tears of £24,473 per QALY gained when using the post hoc CSF‑OSDI definition of response. When using the trial CFS‑OSDI definition of response, ciclosporin plus artificial tears was dominated by vehicle plus artificial tears (that is, was more expensive and less effective than vehicle plus artificial tears).

3.34 Cumulatively applying the ERG's changes to the company's model (in terms of age‑gender modelling, stopping treatment, treatment costs, responder utilities by treatment group, artificial tear use and a small amendment in discounting) produced an ICER of £53,378 per QALY gained for ciclosporin plus artificial tears compared with vehicle plus artificial tears when using the post hoc CFS‑OSDI definition of response. When using the trial CFS‑OSDI definition of response, the cumulative effect of these amendments resulted in ciclosporin being dominated by vehicle plus artificial tears.

3.35 The ERG carried out an exploratory cost‑minimisation analysis comparing ciclosporin with other pharmaceutical formulations of ciclosporin. The results showed that ciclosporin (Ikervis) is less costly (£72 monthly) than Restasis (£119.75 monthly) but more costly than the other 2 ciclosporin formulations currently used in clinical practice in the NHS (Optimmune 0.2% CsA ointment: £55.24 monthly; 2% CsA drops: £47.24 monthly).

Company's response to the Committee's request

3.36 The company, in response to consultation, provided a response to all the Committee's requests described in the appraisal consultation document. It did an updated systematic review with the aim of conducting an indirect treatment comparison of the clinical effectiveness of ciclosporin plus corticosteroids (if needed) and artificial tears, and that of corticosteroids (if needed) plus artificial tears. However, the company stated that a robust indirect comparison was not possible because of methodological problems and the evidence available.

3.37 The company also presented a revised economic analysis of the cost effectiveness of ciclosporin plus corticosteroids (if needed) and artificial tears, and corticosteroids (if needed) plus artificial tears addressing the Committee's request. This cost‑effectiveness analysis included:

3.38 The company did regression analysis to determine which CFS‑OSDI definition of response (the original or the post‑hoc definition of response) was a stronger predictor of change from baseline utility at 6 months and found that the effect on utility was greater with the post‑hoc definition of response. The company therefore concluded that it was more appropriate to use the post-hoc definition of response in the economic analysis.

3.39 The company also did a regression analysis to determine the impact of Sjögren's Syndrome on utility and concluded that it did not affect health‑related quality of life. The company also did a regression analysis to determine whether Sjögren's syndrome had an impact on response. The results showed that Sjögren's syndrome was a statistically significant predictor of response at baseline and at 6 months using the original CFS‑OSDI response definition and at 3 months using the post‑hoc CFS‑OSDI response definition.

3.40 The company noted that because of the lack of clinical evidence for the comparison of ciclosporin plus corticosteroids (if needed) and artificial tears, with corticosteroids (if needed) and artificial tears, corticosteroids were included in the revised model as a cost parameter only. Based on clinical opinion, the company assumed the composition of corticosteroids to be flouromethalone and prednisolone and duration of treatment with corticosteroids to be 8 weeks. The company also assumed that people whose disease responded to treatment were less likely to need corticosteroids (10% of patients whose disease responded to treatment and 30% of patients whose disease did not respond to treatment).

3.41 The company's revised cost‑effectiveness analysis when using the post‑hoc CFS‑OSDI response definition and applying a stopping rule based on the assessment of CFS‑OSDI response at 6 months as per its original analysis produced an ICER for ciclosporin plus corticosteroids (if needed) and artificial tears compared with vehicle plus corticosteroids (if needed) and artificial tears of £14,517 per QALY gained, with an associated incremental cost of £709 and 0.05 additional QALYs. When using the trial CFS‑OSDI response definition the ICER was £45,554 per QALY gained, with an associated incremental cost of £1161 and 0.03 additional QALYs.

3.42 The company also presented a revised cost‑effectiveness analysis applying a stopping rule based on the assessment of CFS‑OSDI response at 3 months instead of at 6 months as per its original analysis. The ICER for ciclosporin plus corticosteroids (if needed) and artificial tears compared with vehicle plus corticosteroids (if needed) and artificial tears when this assumption was applied was £33,432 per QALY gained, with an associated incremental cost of £425 and 0.01 additional QALYs. When using the trial CFS‑OSDI response definition the ICER was £24,696 per QALY gained, with an associated incremental cost of £627 and 0.03 additional QALYs.

3.43 The company noted that a gain in utility was seen for people whose disease responded to treatment, regardless of the treatment regimen or response definition. Treatment did not show a significant effect on utility (p=0.935), and the company considered that the observed differences in utility between the ciclosporin and vehicle groups were circumstantial. Therefore, the company concluded that it was more appropriate to use pooled utility values in the model.

3.44 The company presented a subgroup analysis for people with Sjögren's syndrome which resulted in an ICER for ciclosporin plus corticosteroids (if needed) and artificial tears compared with vehicle plus corticosteroids (if needed) and artificial tears of £16,231 per QALY gained when using the post‑hoc CFS‑OSDI response definition, and of £44,874 per QALY gained when using the original trial definition of response.

3.45 The company also presented a cost‑minimisation analysis comparing different formulations of ciclosporin, assuming that each had equivalent efficacy, adverse event profiles and secondary costs. It noted that the 2% ciclosporin drops formulation developed by Moorfields Pharmaceuticals is no longer available and so the company did not include it in the analysis. The results showed that ciclosporin (Ikervis) is less costly (£72.00 monthly) than Restasis (£454.20 monthly) and Optimmune 0.2% ointment (£227.10 monthly).

ERG comments on company's response to the Committee´s request

3.46 The ERG agreed with the company that it was not possible to do a robust indirect treatment comparison and confirmed that all the requested amendments had been applied in the company's revised cost‑effectiveness analysis. However, the ERG considered that the company's revised method for assuming that ciclosporin is dispensed and costed monthly was not accurate. It instead applied its preferred method, incorporating 2 modifications that relate to drug costs during and after the clinical trial.

3.47 The ERG noted that the company provided results of regression analyses which supported the use of pooled utility values instead of treatment‑specific utility values. The ERG noted that the utility gained from a confirmed response to treatment was substantially greater with vehicle (gain at 6 months=0.095) than with ciclosporin (gain at 6 months=0.056) and considered that pooling the utility values from both treatment groups introduced bias into the cost‑effectiveness analysis, underestimating the utility gain in the vehicle group and overestimating the utility gain in the ciclosporin group. The ERG noted that assuming treatment‑specific utility values had a substantial impact on the cost‑effectiveness results.

3.48 The ERG presented a preferred scenario analysis that included:

3.49 The ERG noted that the company's cost-minimisation analysis results were different from the ERG's results of the analysis presented in the original ERG report (see section 3.37). In particular, the ERG noted that the company concluded that ciclosporin (Ikervis) was over £150 less costly than Optimmune and £382 less costly than Restasis per month. The ERG was unable to validate the source of these data, but suggested that the discrepancy may be because the company assumed that patients have 1 vial of Restasis or 1 tube of Optimmune every week, rather than 1 vial or tube per month.

3.50 Full details of all the evidence are in the Committee papers.