4 Consideration of the evidence

4.1

The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of ranibizumab, having considered evidence on the nature of choroidal neovascularisation associated with pathological myopia and the value placed on the benefits of ranibizumab by people with the condition, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources.

4.2

The Committee considered the current management of visual impairment caused by choroidal neovascularisation associated with pathological myopia. The clinical specialist stated that verteporfin photodynamic therapy (vPDT) has been used since 2005, and before this, no treatment was available. It heard from the clinical specialist that vPDT is not effective in most patients. The Committee discussed the use of vPDT and noted that its use is now diminishing because of the anti‑vascular endothelial growth factor (anti‑VEGF) treatments, such as ranibizumab and bevacizumab. It noted that bevacizumab is used outside of its marketing authorisation and has to be formulated under a 'specials' licence. It concluded that a licensed alternative treatment to vPDT for visual impairment caused by choroidal neovascularisation with pathological myopia would be welcomed by clinicians and patients.

4.3

The Committee considered the impact of visual impairment caused by choroidal neovascularisation with pathological myopia on the everyday life of patients. The Committee understood from the patient expert that the condition affects a younger group of patients compared with other eye conditions and so affects the ability to work, drive, and care for children or other dependents. It heard from the patient expert that loss of vision has a significant effect on the independence of people with the condition and can lead to depression. The Committee agreed that loss of vision caused by choroidal neovascularisation seriously impairs quality of life.

4.4

The Committee considered the comparators for this appraisal. The Committee expressed concern that the manufacturer had not included bevacizumab as a comparator. It noted that the scope listed vPDT and bevacizumab as comparators, although it was aware that bevacizumab does not have a marketing authorisation for treating visual impairment caused by choroidal neovascularisation associated with pathological myopia. The Committee noted that appropriate comparators should be established practice in England. This is not intended to be restrictive, but to emphasise the need for comparison with all relevant comparators; any drug in routine use or considered to be best practice should be considered a potential comparator. The Committee heard from the manufacturer that it considered that bevacizumab was not an appropriate comparator because its use in the NHS is not routine or best practice. The Committee heard from the patient expert and clinical specialist that bevacizumab is used in some patients, but only after some delay to agreement for funding. The Committee noted that the written statements submitted by the Royal College of Ophthalmologists, the Royal College of Pathologists, and the Macular Society suggested considerable use of bevacizumab in the NHS for this indication. The Committee also noted that there are 2 trials (see section 4.7) that compared ranibizumab with bevacizumab in choroidal neovascularisation associated with pathological myopia. However, both of these had a small number of patients. The Committee heard from the clinical specialist that there are some residual safety concerns with the use of bevacizumab, but considered these to be minor. It was aware of the conclusions of the Decision Support Unit report on bevacizumab in eye conditions, which stated that adverse event rates were low in all bevacizumab and comparator groups. However, the Committee also noted that the use of bevacizumab in the eye had not been assessed by the regulatory agencies. It agreed that bevacizumab was a legitimate potential comparator with respect to its use in the NHS. The Committee concluded that because the available evidence for bevacizumab in this indication was limited to 2 small trials, there was currently insufficient evidence to allow bevacizumab to be included with confidence in a clinical and cost‑effectiveness analysis, but it did not rule out the possibility of future evidence providing that confidence.

Clinical effectiveness

4.5

The Committee considered the evidence presented by the manufacturer on the clinical effectiveness of ranibizumab. The Committee acknowledged that the evidence was primarily from RADIANCE, which compared ranibizumab with vPDT, and was complemented by evidence from 2 other randomised trials that compared ranibizumab with bevacizumab, even though the manufacturer did not present the data for the bevacizumab arms of these trials in its submission. The Committee noted that ranibizumab was associated with a greater improvement than vPDT in best corrected visual acuity (BCVA) between baseline and months 1 to 3. The Committee concluded that ranibizumab is a clinically effective treatment option for visual impairment caused by choroidal neovascularisation associated with pathological myopia.

4.6

The Committee discussed the primary end point of RADIANCE, which was the mean average change in BCVA between baseline and months 1 to 3. The Committee heard from the clinical specialist that 3 months was not a long time period to assess the longer-term benefits of ranibizumab. However, the other studies of ranibizumab and the long‑term follow‑up of its use in other eye conditions suggest a sustained effect. The Committee concluded that, because the clinical effectiveness of ranibizumab was not compared with vPDT after 3 months in RADIANCE, there is uncertainty about the long‑term efficacy of ranibizumab for visual impairment caused by choroidal neovascularisation associated with pathological myopia.

4.7

The Committee considered the 2 trials presented in the manufacturer's submission that compared the use of ranibizumab and bevacizumab in choroidal neovascularisation associated with pathological myopia. The Committee noted that this was in line with the scope, in which bevacizumab was included as a comparator. The Committee heard from the clinical specialist that the 2 trials, although small, showed ranibizumab and bevacizumab to be equally effective. It was aware that the manufacturer presented only the results from the ranibizumab arms of these trials in their submission and that the Evidence Review Group (ERG) had presented the results from the bevacizumab arms in their report (see section 3.19). The Committee concluded that ranibizumab is likely to be as clinically effective as bevacizumab in patients with visual impairment caused by choroidal neovascularisation associated with pathological myopia.

4.8

The Committee considered the trial evidence for adverse events associated with ranibizumab. The Committee discussed whether geographic atrophy was under‑reported because markers of this effect were not measured in RADIANCE. The clinical specialist argued that there was no particular reason to expect geographic atrophy as a side effect of ranibizumab treatment. The Committee was aware that the main adverse events listed in the summary of product characteristics were eye pain, ocular hyperaemia, increased intraocular pressure, vitritis, and vitreous detachment. The Committee agreed that the evidence suggested manageable adverse events with ranibizumab, and concluded that ranibizumab was safe and well tolerated in patients with visual impairment caused by choroidal neovascularisation associated with pathological myopia.

Cost effectiveness

4.9

The Committee considered the cost‑effectiveness evidence presented in the manufacturer's submission, including the base‑case results, the sensitivity and scenario analyses and the ERG's critique of the manufacturer's evidence. It noted that the manufacturer had not included bevacizumab as a comparator in its economic model. The Committee understood that the manufacturer's base‑case analysis showed that ranibizumab dominated vPDT (that is, it was more effective and less costly), resulting in more quality‑adjusted life years (QALYs; 13.18 compared with 12.75) and lower costs (£9694 compared with £12,455).

4.10

The Committee accepted the model structure, but was concerned by some of the uncertainties about the assumptions used by the manufacturer. In particular, the Committee queried:

  • the larger proportion of patients with subfoveal involvement at baseline in the VIP trial than in the RADIANCE trial

  • the assumption of an indefinite duration of benefit of ranibizumab treatment

  • the low number of ranibizumab injections needed in year 2 of treatment

  • the high estimated costs of blindness

  • the low estimated costs of ranibizumab and vPDT administration

  • the lack of clarity about the source of the mortality multipliers used in the model

  • the underestimated changes in net QALY gains and the cost of blindness resulting from the method used to account for the possibility of the treated eye changing from being the better‑seeing eye to being the worse‑seeing eye

  • the use of Czoski‑Murray et al. (2009) as a source of utility values, rather than the EQ‑5D data collected in RADIANCE.

    The Committee considered each of these issues in turn, as detailed below.

4.11

The Committee considered the clinical‑effectiveness data that were used in the manufacturer's economic model. It recognised that the clinical‑effectiveness data for ranibizumab were derived from RADIANCE and the data for vPDT after 3 months were derived from the VIP trial. The Committee noted that there was a larger proportion of patients at baseline with subfoveal involvement in VIP compared with RADIANCE and it was concerned that this might have had an impact on the model. The Committee heard from the clinical specialist that an imbalance would only be clinically relevant if it was in the number of patients with extra‑foveal involvement, and that this did not appear to be the case. The Committee concluded that the imbalance in the number of patients with subfoveal involvement in RADIANCE and VIP was unlikely to have a large impact on the manufacturer's model.

4.12

The Committee discussed the manufacturer's assumption that the average BCVA gain at the end of year 1 would continue indefinitely. The Committee heard from the clinical specialist that data collected at the 3 time points in RADIANCE showed that the benefit of ranibizumab was maintained for at least 12 months. The Committee noted that the ERG's sensitivity analyses included different durations of treatment benefit, and that ranibizumab dominated vPDT even when the duration of treatment benefit was reduced to 1 year. The Committee concluded that the duration of treatment benefit was likely to be less than the manufacturer's assumption of an indefinite duration, and that ranibizumab dominated vPDT when the duration of effect was reduced.

4.13

The Committee discussed the manufacturer's assumption about the number of ranibizumab injections that people would receive in clinical practice. The Committee heard from the clinical specialist that, on average, patients only need ranibizumab injections in the first 3 months of their first year of treatment. The clinical specialist also stated that patients in the REPAIR trial had well-preserved eyesight after 18 months and did not need further treatment. The Committee noted that the ERG had increased the number of ranibizumab injections in the second year of ranibizumab treatment from 1.0 to 1.7 in its exploratory analysis. Based on experience with patients using ranibizumab, the clinical specialist felt that this number could be too high. The Committee concluded that the number of injections included in the manufacturer's base case could be an underestimate and that even if the number of injections was increased, ranibizumab would continue to dominate vPDT.

4.14

The Committee considered the costs of blindness used in the manufacturer's economic model. It noted that the ERG presented lower costs of blindness in their report. The Committee heard from the ERG that the difference in the costs of blindness was mainly related to the way the costs for private residential care were calculated. The Committee noted that the manufacturer's sensitivity analysis showed that the model was not sensitive to changes in the costs of blindness. The Committee concluded that the ERG's assumptions about the costs of blindness were likely to be more realistic than those used by the manufacturer, and that if the ERG's assumptions had been used, ranibizumab would continue to dominate vPDT.

4.15

The Committee discussed the administration costs of ranibizumab used in the manufacturer's economic model. It noted that these costs were likely to be an underestimate of the true costs incurred in the NHS. The Committee recognised that the manufacturer's sensitivity analysis showed that the model was not sensitive to changes in the administration costs. The Committee concluded that although some uncertainty remained about the NHS costs involved in the administration of ranibizumab, the uncertainty was not great enough to affect the dominance of ranibizumab over vPDT.

4.16

The Committee discussed the mortality multipliers that the manufacturer had used in its economic model. It heard from the ERG that the source of some of the mortality multipliers was unclear. The ERG also stated that changing the mortality multipliers to alternative values had little impact on the cost savings or QALYs for ranibizumab. The Committee concluded that the manufacturer's rationale for some of the mortality multipliers used in their model was unclear, and that any changes to them were unlikely to change the dominance of ranibizumab over vPDT.

4.17

The Committee considered the method used in the manufacturer's economic model to account for the possibility of the treated eye changing from being the better‑seeing eye to being the worse‑seeing eye as patients changed health states. The Committee understood that the way the manufacturer had modelled this seemed to underestimate the changes in net QALY gains and costs of blindness that may arise from the more effective treatment. The Committee noted that it was not possible to quantify the size of the effect on the base‑case analysis. The Committee concluded that the modelling of the treated eye changing from being the better‑seeing eye to being the worse‑seeing eye as patients changed health states may have had an impact on the base‑case analysis, which showed that ranibizumab dominated vPDT, although the level of impact remained unclear.

4.18

The Committee discussed the utility values used in the manufacturer's economic model. The Committee noted that the source of utility data used in the base‑case analysis (Czoski‑Murray et al. 2009) was used in NICE's technology appraisal guidance on ranibizumab for the treatment of diabetic macular oedema, ranibizumab for treating visual impairment caused by macular oedema secondary to retinal vein occlusion and aflibercept solution for injection for treating wet age-related macular degeneration. It was aware that EQ‑5D data were also collected in RADIANCE, but these data were not used in the model. The Committee heard from the manufacturer that the EQ‑5D data from RADIANCE were not included because the EQ‑5D is widely recognised as not being sensitive in studies of eye conditions. The Committee heard from the ERG that using the EQ‑5D data collected in RADIANCE did not have a large effect on the model, although the effect for the worse‑seeing eye was not clear. The Committee concluded that using the EQ‑5D data from RADIANCE was unlikely to change the overall results of the base‑case analysis and that ranibizumab would continue to dominate vPDT.

4.19

The Committee noted that the manufacturer's model had not included bevacizumab as a comparator and so the base‑case analysis was limited to a comparison of ranibizumab with vPDT. However, because the available evidence for bevacizumab in this indication was limited to 2 small trials (see section 4.4), there was currently insufficient evidence to allow bevacizumab to be included with confidence in a clinical and cost‑effectiveness analysis. The Committee considered the uncertainties in the manufacturer's model and noted that they did not have an effect on the overall results of the base‑case analysis, which showed that ranibizumab dominated vPDT. The Committee concluded that ranibizumab was a cost‑effective use of NHS resources for treating people with visual impairment caused by choroidal neovascularisation associated with pathological myopia when vPDT was the comparator.

4.20

The Committee discussed how innovative ranibizumab is in its potential to make a significant and substantial impact on health‑related benefits. It agreed that anti‑VEGF treatments, such as ranibizumab, were a substantial improvement over previous treatments, and considered that this improvement applied to the class of drugs, including bevacizumab. It stated that the innovation was a step forward in providing health‑related patient benefits, not the act of licensing. In addition there were no substantial benefits of ranibizumab over its comparators that were not already captured in the QALY estimation in the modelling. The Committee discussed whether NICE's duties under the equalities legislation required it to alter or add to its recommendations in any way. No equality issues were raised during the appraisal process or at the Committee meeting. Therefore, the Committee concluded that no alterations or additions to its recommendations were needed.

Summary of Appraisal Committee's key conclusions

Key conclusion (sections 1.1, 3.4, 3.15, 3.16, 4.5, 4.6, 4.9, 4.19)

Ranibizumab is recommended as an option for treating choroidal neovascularisation associated with pathological myopia when the manufacturer provides ranibizumab with the discount agreed in the patient access scheme.

The clinical evidence from RADIANCE, which compared ranibizumab with vPDT, showed that ranibizumab was associated with a greater improvement than vPDT in BCVA between baseline and months 1 to 3, although there is uncertainty about the efficacy after 3 months. The Committee concluded that ranibizumab is a clinically effective treatment option for visual impairment caused by choroidal neovascularisation associated with pathological myopia.

The key drivers of the cost‑effectiveness analysis included the unit cost of ranibizumab and vPDT, the number of ranibizumab injections in the first and second year, the starting age of the patient group, the discount rate for benefits and the maximum utility gain in the worse‑seeing eye. The manufacturer's base‑case cost‑effectiveness analysis showed that ranibizumab dominated vPDT, resulting in more QALYs and lower costs. The Committee concluded that the uncertainties associated with the key drivers in the model were unlikely to have an effect on the overall cost‑effectiveness results. The Committee therefore recommended ranibizumab as a cost‑effective use of NHS resources.

Current practice

Clinical need of patients, including the availability of alternative treatments (sections 4.2 to 4.4)

The Committee heard that visual impairment caused by choroidal neovascularisation seriously impairs quality of life.

The Committee heard that the current standard treatment for choroidal neovascularisation secondary to pathological myopia is vPDT. However, it is not effective in most patients and its use is diminishing because of anti‑VEGF treatments.

The Committee heard from a clinical specialist that the non‑licensed use of bevacizumab in the NHS is not routine or best practice. However, written statements from the Royal College of Ophthalmologists, the Royal College of Pathologists, and the Macular Society suggested considerable use of bevacizumab in the NHS for this indication.

The Committee heard from the patient expert and the clinical specialist that there are often delays in agreements to fund ranibizumab or bevacizumab.

The technology

Proposed benefits of the technology; how innovative is the technology in its potential to make a significant and substantial impact on health-related benefits? (section 4.20)

The Committee agreed that anti‑VEGF treatments (such as ranibizumab) were a substantial improvement over previous treatments.

It was not aware of any substantial benefits of ranibizumab over its comparators that were not already captured in the QALY estimation in the modelling.

What is the position of the treatment in the pathway of care for the condition? (section 4.5)

The Committee assessed the clinical effectiveness of ranibizumab compared with vPDT for treating visual impairment caused by choroidal neovascularisation associated with pathological myopia.

Adverse reactions (section 4.8)

The Committee was aware that the main adverse events listed in the summary of product characteristics were eye pain, ocular hyperaemia, increased intraocular pressure, vitritis, and vitreous detachment. The Committee agreed that the evidence suggested manageable adverse events with ranibizumab, and concluded that ranibizumab was safe and well tolerated in patients with visual impairment caused by choroidal neovascularisation associated with pathological myopia.

Evidence for clinical effectiveness

Availability, nature and quality of evidence (sections 4.4 to 4.5)

The Committee acknowledged that the evidence presented by the manufacturer was primarily from RADIANCE, which compared ranibizumab with vPDT. This evidence was complemented by data from the ranibizumab arm of 2 other randomised trials.

The Committee was aware that the scope of the appraisal listed bevacizumab as a comparator. It noted that the ERG identified only 2 small trials that compared ranibizumab and bevacizumab. The Committee concluded that there was currently insufficient evidence to allow bevacizumab to be included with confidence in a clinical and cost‑effectiveness analysis.

Relevance to general clinical practice in the NHS (section 4.2)

The Committee heard that the current standard treatment for visual impairment caused by choroidal neovascularisation secondary to pathological myopia is vPDT. However, it is not effective in most patients and its use is diminishing because of anti VEGF treatments, such as ranibizumab and bevacizumab.

Uncertainties generated by the evidence (section 4.6)

The Committee noted that the primary end point of RADIANCE was the mean average change in BCVA between baseline and months 1 to 3. The Committee heard from a clinical specialist that 3 months was not a long time period to assess the longer-term benefits of ranibizumab. The Committee concluded that, because the clinical effectiveness of ranibizumab was not compared with vPDT after 3 months, there is uncertainty about the long‑term efficacy of ranibizumab for choroidal neovascularisation associated with pathological myopia.

Are there any clinically relevant subgroups for which there is evidence of differential effectiveness?

None.

Estimate of the size of the clinical effectiveness including strength of supporting evidence (section 4.5)

The Committee noted that ranibizumab was associated with a greater improvement than vPDT in BCVA between baseline and months 1 to 3. The Committee concluded that ranibizumab is a clinically effective treatment option for visual impairment caused by choroidal neovascularisation associated with pathological myopia.

Evidence for cost effectiveness

Availability and nature of evidence (sections 4.9 to 4.10)

The Committee considered the manufacturer's economic model and the critique and exploratory analyses performed by the ERG. It accepted the model structure, but was concerned by some of the uncertainties about the assumptions used by the manufacturer.

The Committee noted that the manufacturer had not included bevacizumab as a comparator in its economic model.

Uncertainties around and plausibility of assumptions and inputs in the economic model (sections 4.11 to 4.18)

The Committee considered the larger proportion of patients with subfoveal involvement in the VIP trial, which provided the vPDT data after 3 months. However, it concluded that the imbalance between RADIANCE and VIP was unlikely to have a large impact on the manufacturer's model.

The Committee considered the manufacturer's assumption that the average BCVA gain at the end of year 1 would continue indefinitely. It concluded that the duration of treatment benefit was likely to be less than the manufacturer's assumption of an indefinite duration, but that ranibizumab dominated vPDT when the duration of effect was reduced.

The Committee discussed whether the manufacturer's assumption about the number of ranibizumab injections that people would receive in clinical practice was too low. It concluded that the number of injections included in the manufacturer's base case could be an underestimate, and that even if the number of injections was increased, the base‑case analysis would not be affected.

The Committee discussed whether the costs of blindness used in the manufacturer's model were too high. The Committee noted that the ERG presented lower costs of blindness in their report. The Committee concluded that the ERG's assumptions about the costs of blindness were likely to be more realistic than those used by the manufacturer, and that any changes were unlikely to have a large impact on the base‑case analysis.

The Committee discussed whether the administration costs of ranibizumab used in the manufacturer's model were an underestimate. It concluded that the NHS costs were uncertain, but the uncertainty was not great enough to affect the base‑case analysis.

The Committee discussed whether the mortality multipliers used in the manufacturer's economic model were appropriate. It concluded that the manufacturer's rationale for some of the mortality multipliers in the model was unclear, and that any changes to them were unlikely to change the base‑case analysis.

The Committee discussed whether the method used in the manufacturer's model to account for the possibility of the treated eye changing from being the better‑seeing eye to the worse‑seeing eye as patients change health states was appropriate. It concluded that the modelling may have had an impact on the base‑case analysis, but the level of impact was unclear.

The Committee considered that EQ‑5D data were collected in RADIANCE, but were not used in the manufacturer's economic model. It concluded that using the EQ‑5D data from RADIANCE was unlikely to change the overall results of the base‑case analysis.

Are there specific groups of people for whom the technology is particularly cost effective?

None.

What are the key drivers of cost effectiveness? (section 3.16)

The manufacturer's sensitivity analyses showed that the cost effectiveness of ranibizumab was sensitive to changes in the unit cost of ranibizumab and vPDT, the number of ranibizumab injections in the first and second year, the starting age of the patient group, the discount rate for benefits, and the maximum utility gain in the worse‑seeing eye.

Most likely cost-effectiveness estimate (given as an ICER; sections 4.9, 4.11 to 4.19)

The Committee noted that manufacturer's base-case analysis showed that ranibizumab dominated vPDT (that is, it was more effective and less costly), resulting in more QALYs (13.18 compared with 12.75) and lower costs (£9694 compared with £12,455). The Committee considered the uncertainties in the manufacturer's model and noted that they were unlikely to have an effect on the overall results of the base-case analysis, which showed that ranibizumab dominated vPDT.

Additional factors taken into account

Patient access schemes (section 2.4)

The Department of Health and the manufacturer have agreed that ranibizumab will be available to the NHS with a patient access scheme which makes ranibizumab available with a discount. The level of discount is commercial in confidence.

End-of-life considerations

Not applicable.

Equalities considerations and social value judgements (section 4.21)

No equality issues were raised during the appraisal process or at the Committee meeting. Therefore the Committee concluded that no alterations or additions to its recommendations were needed.

  • National Institute for Health and Care Excellence (NICE)