Fluocinolone acetonide intravitreal implant for treating recurrent non-infectious uveitis

People with recurrent non-infectious uveitis affecting the posterior segment of the eye will welcome a new treatment option

3.1 Patient experts described the anxiety associated with having uveitis because of potentially worsening sight, if they will be able to continue working and how it affects their relationships and independence. They explained that existing treatments for controlling recurrent non-infectious uveitis can be burdensome and disruptive to daily life for both patients and their carers, needing frequent hospital visits for administration and monitoring. The patient experts described how having a treatment that lasts for 3 years had substantially increased their quality of life. They highlighted that the fluocinolone acetonide implant could be particularly beneficial for people who cannot have systemic treatments, such as pregnant women. One of the patient experts described how the effects of the dexamethasone implant had lasted for much less than the 6 months they had been expecting. The clinical experts also highlighted that biologic treatments are not effective in 20% to 30% of patients with recurrent non-infectious uveitis and there is a need for alternative treatment options. The committee concluded that people with recurrent non-infectious uveitis affecting the posterior segment of the eye would welcome an additional treatment option, particularly one with long-lasting benefits.

The dexamethasone implant is a relevant comparator

3.2 The clinical experts explained that non-infectious uveitis is treated differently depending on whether the disease is:

There may also be local variation in treatment. Non-infectious uveitis without systemic disease may first be treated with local corticosteroids, followed by systemic corticosteroids or a dexamethasone implant. Multiple repeated dexamethasone implants may be given. Bilateral disease or unilateral disease with active systemic disease may first be treated with systemic corticosteroids, followed by immunosuppressants or dexamethasone implants. Treatments may also be used in combination. TNF-alpha inhibitors such as adalimumab may be an option after immunosuppressants. The anticipated marketing authorisation for the fluocinolone acetonide implant is for recurrent disease, so the clinical experts explained that they would most likely offer it to patients who had already had corticosteroids. They explained that if the disease responded well to a dexamethasone implant, they would consider using a fluocinolone acetonide implant instead of another dexamethasone implant. The committee agreed that in NHS clinical practice in England, it was likely that the fluocinolone acetonide implant would be used after corticosteroids, as an alternative to the dexamethasone implant. The committee concluded that the dexamethasone implant was a relevant comparator for the fluocinolone acetonide implant.

The clinical trial does not reflect NHS clinical practice in England

3.3 The evidence for the fluocinolone acetonide implant came from the PSV-FAI-001 trial. This was a multicentre, randomised, double-blind trial in patients with chronic non-infectious uveitis affecting the posterior segment of the eye. It compared the fluocinolone acetonide implant with a sham injection. Patients in both treatment groups could have 'limited current practice': this was the corticosteroids and immunosuppressants that they had been having before enrolling in the trial, but tapered off within the first 3 months. Other than treatments that were being tapered off, patients could not have corticosteroids or immunosuppressants until their uveitis recurred. This meant that after 3 months and before recurrence, people in the control group had no treatment, which does not reflect treatment in NHS clinical practice in England. Additionally, before recurrence in the trial, systemic treatment could only be used after local treatment had failed. The committee agreed that this did not reflect clinical practice in the NHS in England because the clinical experts had said that systemic treatment may be given first for bilateral or systemic disease (see section 3.2). The committee concluded that treatment in the trial did not reflect NHS clinical practice in England.

Rates of recurrence of uveitis in the trial are likely overestimated

3.4 The primary outcome in the PSV-FAI-001 trial was the proportion of patients who had a recurrence of uveitis in the study eye within 6 months of having study treatment. After 12 months, the recurrence rate was 37.9% in the fluocinolone acetonide implant group and 97.6% in the control group. However, the committee noted that recurrence was assumed for patients who had missing data for the required eye examinations, or who had local or systemic treatments that were prohibited as part of the trial. The trial did not record why prohibited treatments were given, but the committee considered that they may have been used to treat the other eye or for an underlying condition (rather than for recurrent uveitis in the study eye). So, it agreed that the recurrence rates reported in the trial were likely overestimated.

It is possible that the fluocinolone acetonide implant improves visual acuity but not all relevant evidence was presented

3.5 Visual acuity was a secondary outcome in the PSV-FAI-001 trial. After 12 months, mean best-corrected visual acuity (BCVA) in the control group had increased from 64.9 letters to 69.2 letters. In the fluocinolone acetonide implant group, mean BCVA increased from 66.9 letters to 72.8 letters. The clinical experts explained that a 5-letter increase in BCVA is clinically meaningful. They highlighted that most of the people in the control group had had a recurrence of uveitis by 12 months, so would have had other treatments, which could explain the increase in BCVA in this group. The ERG highlighted that the company had not reported the results of any tests for statistical significance, so it was difficult to compare the change in BCVA between the 2 groups. The company stated that these tests had been done, but it had not reported the results in its submission. The committee noted that visual acuity was not included in the model. However, it requested that the company provide all relevant results of statistical tests. The committee concluded that it was possible that the fluocinolone acetonide implant improves visual acuity compared with current practice, but that it had not been presented with all relevant evidence.

Adverse effects associated with the fluocinolone acetonide implant are manageable in clinical practice

3.6 Common adverse effects of the fluocinolone acetonide implant include cataract and increased intraocular pressure. One of the patient experts explained that although developing a cataract did affect their sight, which reduced their quality of life, the cataract surgery was relatively straightforward and it did not have a lasting effect on their quality of life. The clinical experts stated that there was unlikely to be a big difference in the adverse effects of the fluocinolone acetonide implant compared with those of the dexamethasone implant. The committee noted that including disutilities for adverse effects in the cost-effectiveness model had a big effect on the cost-effectiveness results (see section 3.12). The committee noted that there were more older people in the control group of the trial, which may have affected the rate of adverse effects compared with that in the fluocinolone acetonide implant group. But overall, the committee considered that the fluocinolone acetonide implant is well tolerated compared with other treatments for uveitis and that the adverse effects are manageable in clinical practice.

The model should consider both eyes

3.7 The company presented a Markov model with 5 health states: on treatment, subsequent therapy, remission, permanent blindness and death. The model compared the fluocinolone acetonide implant with the treatments received in the control group in the PSV-FAI-001 trial (described as 'limited current practice', see section 3.3) in the study eye only. Treatment effectiveness was modelled using time to first uveitis recurrence in the study eye from the trial. The ERG highlighted that in a potentially bilateral disease, modelling should consider both eyes to fully capture the effect of sight loss on health-related quality of life, survival and costs. The clinical experts suggested that a large proportion of people with recurrent non-infectious uveitis have bilateral disease. In the trial, 67.8% in the fluocinolone acetonide implant group and 73.8% in the control group had bilateral disease at baseline. The committee concluded that the model should consider both eyes.

The dexamethasone implant should be a comparator in the model

3.8 Based on the clinical experts' description of the treatment pathway, the committee considered that the dexamethasone implant was a relevant comparator for the fluocinolone acetonide implant (see section 3.2). The ERG did a naive analysis, estimating the potential effectiveness of the dexamethasone implant compared with limited current practice (based on evidence used to inform NICE technology appraisal guidance on adalimumab and dexamethasone for treating non-infectious uveitis) so that it could include the dexamethasone implant in the model as a comparator. The analysis assumed that the dexamethasone implant was more effective than limited current practice, with a hazard ratio for time to first recurrence of 0.456. The clinical experts suggested that they expected the effectiveness of the fluocinolone acetonide implant to be similar to that of the dexamethasone implant. The committee noted that the benefit of the dexamethasone implant lasted for almost 6 months in the model, whereas patient experts had experience of the implant lasting less than 6 months (see section 3.1). The patient experts explained that repeated dexamethasone implants can only be given after vision has deteriorated, which means a patient may have several weeks of reduced vision between implants. The committee considered that at their best, both the fluocinolone acetonide and dexamethasone implants are likely to have a similar effect on visual acuity, but over 3 years, on average the fluocinolone acetonide implant may be more effective in preventing recurrence of uveitis. The committee recalled the clinical experts' suggestion that if the disease responded well to a dexamethasone implant, they would consider using a fluocinolone acetonide implant instead of another dexamethasone implant (see section 3.2). The committee agreed that it would like to see this reflected in the model. It concluded that it would prefer a model that compared the fluocinolone acetonide implant with the dexamethasone implant, both as single and repeated implants.

The model should not include a remission health state

3.9 In the company's model, patients who did not have a recurrence of uveitis within 2 years were assumed to be in the remission health state, in which their health-related quality of life was the same as the general population. The committee was aware that in the assessment group's model used when developing the NICE technology appraisal guidance on adalimumab and dexamethasone, the remission health state was only used in a scenario analysis. The clinical experts explained that although remission from uveitis is possible, about 30% of people would have a recurrence if treatment were stopped, even if they had not had a recurrence for 2 years. The committee considered it unlikely that everyone who did not have a recurrence of uveitis within 2 years would be in remission. Moreover, even people with uveitis in remission may have lower health-related quality of life than the general population because of bilateral disease or underlying systemic disease. The committee concluded that the model should not include a remission health state.

The model should include the possibility of multiple implants

3.10 The company's model assumed that each patient had only 1 fluocinolone acetonide implant. However, the clinical experts stated that they would consider using another fluocinolone acetonide implant after 3 years, if the disease had responded well to the first implant. The committee concluded that the model should include an option for retreatment with multiple fluocinolone acetonide implants.

Results both with and without a transition from on treatment to permanent blindness should be included

3.11 In the company's model, there was no transition between the on-treatment and permanent blindness health states. The ERG added this transition in its base-case analysis, because it was included in the model used when developing the NICE technology appraisal guidance on adalimumab and dexamethasone. The committee was aware that the company's model was consistent with the results of the PSV-FAI-001 trial. The committee concluded that it would like to see the results both with and without this transition.

The model should not include a treatment benefit with the fluocinolone acetonide implant after 3 years

3.12 The company's model extrapolated the treatment effect of the fluocinolone acetonide implant beyond the 3-year time horizon of the trial, even though the implant only releases fluocinolone acetonide for 3 years. The clinical experts suggested that for some people there may be residual effects of the treatment after 3 years, and there is an ongoing benefit of having had stable disease for 3 years. The committee agreed that it was possible there may be some benefit after 3 years, but that there was no evidence from the trial to support this. It concluded that the model should not include any treatment benefit with the fluocinolone acetonide implant after 3 years.

Disutility values should be calculated based on the length and severity of each adverse event

3.13 The company used health-related quality of life data from the MUST trial because the PSV-FAI-001 trial did not measure it. The MUST trial investigated a higher strength of fluocinolone acetonide implant in the same indication. To calculate utility values for the on-treatment and subsequent therapy health states, the company mapped Visual Function Questionnaire-25 (VFQ-25) data from MUST to the EQ-5D. The ERG highlighted that as well as the implant being a higher strength, the population in MUST was different to that in PSV-FAI-001 (in MUST, 20% of patients had systemic treatment before recurrence, bilateral treatment with the fluocinolone acetonide implant was allowed, and there were fewer people with macular oedema at baseline). For the permanent blindness health state in its base case, the company used a utility value of 0.38, taken from a study by Czoski-Murray et al. (2009). The committee was aware that a utility value of 0.57 from Brown et al. (1999) had been preferred for the permanent blindness health state when developing the NICE technology appraisal guidance on adalimumab and dexamethasone.The committee was also aware that carers' health-related quality of life (see section 3.1) may also be affected, but that it had not been presented with evidence to capture this. The ERG highlighted that the company's model did not include disutilities for adverse events. Because the ERG did not have information on the length and severity of each adverse event, it did 2 exploratory analyses assuming a disutility of 0.05 or 0.10 for every adverse event. This had a large effect on the cost-effectiveness results, but the committee considered these analyses to be speculative and not reliable for decision making. The committee concluded that it would prefer to see disutility values calculated based on the length and severity of each adverse event, and incorporated into the model.

Changes to the costs of permanent blindness and monitoring for immunosuppressants have little effect on the cost-effectiveness results

3.14 In the company's model, the costs in the permanent blindness health state were based on those used when developing the NICE technology appraisal guidance on adalimumab and dexamethasone. These were taken from a population with age-related macular oedema and included costs of hip replacement, community care and residential care. The committee noted that the ERG had excluded these costs for people under 65 years in its changes to the model, because uveitis generally affects a younger population than age-related macular oedema and so these costs would be less relevant. The ERG also included costs of a monitoring blood test every 12 weeks while having immunosuppressants in the subsequent treatment health state. The committee concluded that the ERG's changes to the costs were plausible but they did not have a large effect on the cost-effectiveness results.

The ERG's changes to the company's model increase the ICER

3.15 The company's deterministic base case showed that the incremental cost-effectiveness ratio (ICER) for the fluocinolone acetonide implant compared with limited current practice was £7,183 per quality-adjusted life year (QALY) gained. All analyses included the patient access scheme for the fluocinolone acetonide implant. The ERG presented base-case ICERs ranging from £12,325 (for a single fluocinolone acetonide implant [see section 3.10] and no disutilities for adverse events [see section 3.14]) to £30,153 (including multiple fluocinolone acetonide implants and a disutility of 0.05 for every adverse event) per QALY gained (compared with limited current practice). When the ERG included a disutility of 0.10 for all adverse events, the ICER increased from £12,325 to £85,084 per QALY gained. The ERG also did a naive analysis to include the dexamethasone implant (hazard ratio for time to first recurrence of 0.456 compared with limited current practice, see section 3.8), in which the dexamethasone implant was extendedly dominated (that is, some combination of other treatments would be more cost effective). When the ERG assumed equal efficacy for the fluocinolone acetonide and dexamethasone implants, the dexamethasone implant was dominant compared with the fluocinolone acetonide implant (that is, it was both less costly and more effective). When the ERG assumed that the dexamethasone implant was more effective than the fluocinolone acetonide implant, the fluocinolone acetonide implant was extendedly dominated.

The cost effectiveness of the fluocinolone acetonide implant is uncertain

3.16 The committee accepted some of the changes the ERG made to the company's model, including:

The committee noted that including the ERG's analysis of adverse events had a big effect on the results, representing considerable uncertainty in the modelling of utility values for adverse effects (see section 3.14). The committee also noted that neither the company's nor the ERG's analyses included both eyes (see section 3.7). It agreed that the ERG's analysis including the dexamethasone implant was naive and did not reflect the clinical experts' suggestion that in practice they may use 1 dexamethasone implant before a fluocinolone acetonide implant (see section 3.8). The committee agreed that all the cost-effectiveness estimates were highly uncertain because of the trial results (see sections 3.3 and 3.4). Because of the high level of uncertainty in the clinical and economic evidence, the committee agreed that an acceptable ICER would be around £20,000 per QALY gained (see NICE's guide to the methods of technology appraisal). The committee agreed that the fluocinolone acetonide implant would be a potentially promising treatment for patients, but because of the uncertainty, it concluded that it was minded not to recommend fluocinolone acetonide implant as an option for preventing relapse in recurrent non-infectious uveitis affecting the posterior segment of the eye in adults.

More analyses are needed

3.17 The committee agreed that it would like to see updated analyses that included its preferred assumptions (see sections 3.7 to 3.15). The committee recommended that NICE requests further analyses from the company, as specified in section 1.2, which should be made available for the second appraisal committee meeting.

The benefits of the fluocinolone acetonide implant are captured in the cost-effectiveness analysis

3.18 The company considered the fluocinolone acetonide implant to be innovative. It highlighted that the long-lasting design of the implant could lead to benefits such as a reduced treatment burden and more consistent disease control. The clinical experts also suggested that the implant was innovative because of the potential for 3 years of disease control with 1 implant. The committee concluded that the fluocinolone acetonide implant would be beneficial for patients, but it had not been presented with evidence of any additional benefits that were not captured in the measurement of QALYs.

Any change in recommendations would need to consider potential equality issues

3.19 A stakeholder highlighted that the long-lasting design of the fluocinolone acetonide implant could improve adherence to treatment for some people, such as those with dementia or mental health problems. It was also highlighted that the fluocinolone acetonide implant may be of particular benefit to women who want to start a family or who are pregnant, because systemic treatments would not be suitable. If the committee changes its recommendations, it will need to be mindful of these considerations in its decision making.