Dexamethasone intravitreal implant for treating diabetic macular oedema

Clinical need and practice

2.1 The committee heard from patient experts about the nature of DMO and their experience with treatment. It heard that the loss of vision has a significant impact on a person's independence; for example, it can affect their ability to drive and perform everyday activities such as dressing and making a cup of tea. The patient experts commented that the condition can disrupt employment because of attendance at regular follow up or monitoring appointments and, furthermore, some people may be unable to work or care for family members. The patient experts acknowledged that although an injection into the eye is unpleasant it is not painful, and they are willing to have injections to maintain their sight. They emphasised that the effect of dexamethasone intravitreal implant lasted much longer than anti‑vascular endothelial growth factor (anti-VEGF) treatments. The committee heard from clinical experts that although anti‑VEGF treatments have made a big difference to clinical practice the need for repeat treatment visits is problematic. The committee noted that dexamethasone intravitreal implant is licensed for use every 6 months in line with the MEAD trials (see section 1.2) but heard that it is often given more frequently than this in practice (every 4 months). The committee heard from the clinical and patient experts that there is a clinical need for alternative treatments for people with DMO that is unresponsive to non‑corticosteroid treatment. The committee concluded that patients and clinicians considered dexamethasone intravitreal implant to be a valuable option that could offer longer‑term benefits than anti‑VEGF treatments to some people with DMO, and for people with DMO that is unresponsive to non‑corticosteroid treatment.

2.2 The committee considered which people with DMO would potentially be eligible for treatment with dexamethasone intravitreal implant in clinical practice. The committee recalled that the indication in the marketing authorisation for dexamethasone intravitreal implant was for the treatment of adult patients with visual impairment due to DMO who are pseudophakic or whose DMO is considered insufficiently responsive to, or unsuitable for, non‑corticosteroid therapy. It noted that this was narrower than the general population with DMO which was enrolled in the clinical trials and specified in the final NICE scope, which was finalised before the marketing authorisation was granted. The committee was mindful that it could only make recommendations within the marketing authorisation. After considering comparators within the context of the marketing authorisation (see sections 2.4 and 2.5), it concluded that the 4 potentially eligible populations were:

2.3 The committee considered the clinical pathway for people with DMO in relation to the marketing authorisation for dexamethasone intravitreal implant. It heard from the clinical experts that treatment options vary according to CRT, whether their disease is unresponsive to non‑corticosteroid treatment and whether such treatment is unsuitable for them, and whether a person has a pseudophakic lens.

2.4 The committee discussed the clinical pathway for people based on CRT levels. For people with a CRT of 400 micrometres or more, the clinical experts stated that ranibizumab is given as recommended in NICE's technology appraisal guidance on ranibizumab for treating diabetic macular oedema. For people who have a CRT of less than 400 micrometres, the committee noted that ranibizumab is not recommended in NICE's technology appraisal guidance on ranibizumab for treating diabetic macular oedema and it heard from clinical experts that the prescribing options in clinical practice are laser photocoagulation and bevacizumab (outside its marketing authorisation). The committee heard that bevacizumab was used in some centres and therefore took it into account in its decision‑making.

2.5 The committee discussed the clinical pathway for people with DMO that is insufficiently responsive to non‑corticosteroid therapy (such as ranibizumab, bevacizumab and laser photocoagulation). The committee noted that for people who have a pseudophakic lens and chronic disease, fluocinolone acetonide intravitreal implant is recommended in NICE's technology appraisal guidance on fluocinolone acetonide intravitreal implant for treating chronic diabetic macular oedema after an inadequate response to prior therapy. It heard from the clinical experts that they perceived that fluocinolone acetonide intravitreal implant had been used with caution in the UK because some of its side effects can be difficult to reverse, given its long duration of action. The clinical experts noted that it is given every 36 months, meaning that if intraocular pressure becomes elevated (a class effect of intravitreal corticosteroid treatment), it can be difficult to lower and surgical intervention may be needed. The committee heard from the clinical experts that people with DMO that is insufficiently responsive to non‑corticosteroid therapy who do not have a pseudophakic lens are monitored but do not have active treatment (watch‑and‑wait).

2.6 The committee heard from the clinical experts that there are no clinical criteria for determining whether a treatment is unsuitable for a person with DMO. However, they suggested that treatment with an anti‑VEGF agent (for example, ranibizumab) is likely to be unsuitable for people who cannot attend monthly appointments, people who have had a recent cardiovascular event or stroke, and people who have a phobia of needles.

2.7 The committee considered the most relevant comparators based on the final NICE scope and what it had heard from the clinical experts. The committee concluded that, based on current practice, the relevant comparators for dexamethasone intravitreal implant in the 4 subpopulations of people with DMO (see section 2.2) are as follows:

Clinical effectiveness

2.8 The committee considered the evidence presented by the company on the clinical effectiveness of dexamethasone intravitreal implant. It noted that the main sources of evidence were the MEAD randomised controlled trials, which compared dexamethasone intravitreal implant with sham procedure in a general population of people with DMO (that is, a broader population than that covered by the marketing authorisation). It noted that the company had provided subgroup analyses for people with a pseudophakic lens, but not for people whose condition did not respond to non‑corticosteroid treatment, or for whom it was not suitable. The committee agreed that dexamethasone intravitreal implant resulted in a greater average change in mean best corrected visual acuity (BCVA) than sham procedure for the general DMO population (dexamethasone 3.5 letters versus sham 2.0 letters, p=0.023) and for the subgroup of people with a pseudophakic lens (dexamethasone 6.5 letters versus sham 1.7 letters, p<0.001). The committee concluded that dexamethasone intravitreal implant is a clinically effective treatment for DMO compared with sham procedure.

2.9 The committee considered the high discontinuation rates in the dexamethasone and sham procedure arms in the MEAD trials. It heard from the clinical experts that the duration of the trials was 3 years which was longer than many other clinical trials in DMO populations; this may have resulted in more people dropping out of the trials. It heard from the company that many people in the sham procedure arm withdrew from the trials because their vision did not improve. Furthermore, if patients in the sham procedure arm needed additional treatment for their vision, the treatment was offered and then the patients were excluded from the trial. Therefore, the people in the sham arm of the MEAD trials are unlikely to be a true representation of the people who have watch‑and‑wait in clinical practice, because in practice people would be less likely to expect an improvement and to seek treatment changes. The evidence review group (ERG) noted that people also dropped out of the dexamethasone arm of the trials but to a lesser extent. The committee accepted that people remaining in the sham arm of the MEAD trials may not be representative of people who would have dexamethasone intravitreal implant in clinical practice and concluded that the MEAD trials might have underestimated the benefit of dexamethasone intravitreal implant compared with sham procedure.

2.10 The committee considered the evidence for dexamethasone intravitreal implant and its comparators that was derived from the company's network meta‑analysis. It noted that evidence from direct comparisons was not available for all comparators, so a network meta‑analysis had been carried out by the company. The committee noted the ERG's concerns that there were high levels of clinical and statistical heterogeneity associated with the network meta‑analysis and that there were wide 95% credible intervals around a large number of the relative risk estimates. It further noted that the MEAD trials informed the comparison of dexamethasone intravitreal implant and watch‑and‑wait and questioned whether a network meta‑analysis was necessary when direct trial data was available. It noted that the relative effects in the network meta‑analysis for dexamethasone intravitreal implant compared with sham were calculated using data only from the MEAD trials. The committee concluded that although the company's network‑meta‑analysis was associated with uncertainty, it was acceptable to inform its decision‑making except for the comparison of dexamethasone intravitreal implant with sham (watch‑and‑wait). For this comparison, it concluded that its deliberations should focus on the data from the MEAD trials because these head‑to‑head results were more robust than those of the network meta‑analysis (which were based only on MEAD trial data).

2.11 The committee considered the evidence on adverse events associated with dexamethasone intravitreal implant. It noted that the overall frequency of adverse events in the MEAD trials was acceptable and that there were fewer ocular adverse events in people with a pseudophakic lens compared with the general DMO population. It acknowledged that this was likely to be because cataracts were included as ocular adverse events, and people who have had their lens replaced with a pseudophakic lens cannot develop cataracts. The committee concluded that dexamethasone intravitreal implant had an acceptable adverse event profile in people with DMO.

Cost effectiveness

2.12 The committee considered the cost‑effectiveness analyses presented by the company and the critiques, corrections and exploratory analyses performed by the ERG. The committee noted the following in the company's original submission and analyses supplied in response to clarification:

2.13 The committee considered the cost of residential care in the company's economic model. The ERG noted that the cost of residential care was overestimated which caused the cost of severe vision loss (BCVA less than 35 letters) to be overestimated (see section 1.82). This was a key driver in the model for people with DMO that has not responded adequately to non‑corticosteroid therapy, or for whom such treatment is unsuitable. The committee noted that the company used the cost of local authority care in its model and heard from the ERG that the unit cost of private residential care should have been used in the model (see section 1.82). The committee concluded that the costs of severe vision loss had been overestimated in the company's original calculations.

2.14 The committee considered the utility values used in the company's model. The committee noted that the utility values were based on trial data and spanned a relatively narrow range. The committee discussed that it was possible that the utility values may have underestimated the disability resulting from the worst health state. It acknowledged that the company had not provided any evidence that the utility values used in the model were a good fit to the data nor how the fit would compare with more complex models that allowed interaction between eyes. However, the committee noted that published utility values have a number of limitations; in particular, they are not specific to people with DMO (Brown 1999, Brown et al. 2000, Czoski‑Murray et al. 2009). It heard from the ERG that data from the MEAD trials is likely to be more relevant to people with DMO than the published utility values. The committee acknowledged that the company's approach to inclusion of utility values in the model had some limitations, but so too did the published utility values available. On balance, the committee agreed that the company's utility values were suitable to inform its decision‑making despite these limitations. However, it also concluded that neither approach was ideal and that both had shortcomings that inhibited the accurate estimation of the cost effectiveness of dexamethasone intravitreal implant for DMO.

2.15 The committee considered other elements of the company's model. It acknowledged that the ERG had concerns about several factors that could have biased the results. These included modelling transitions for each eye independently, 'normalising' the transition probabilities in the model to sum them to 1 and assuming that the relative effect of dexamethasone intravitreal implant compared with sham procedure was stable for 3 years:

2.16 The appraisal committee considered whether it should take into account the consequences of the pharmaceutical pricing regulation scheme (PPRS) 2014, and in particular the PPRS Payment Mechanism, when appraising dexamethasone intravitreal implant. 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 dexamethasone intravitreal implant. It therefore concluded that the PPRS Payment Mechanism was irrelevant for the consideration of cost effectiveness of dexamethasone intravitreal implant.