«NICE technology appraisal guidance 155 guidance.nice.org.uk/ta155 NICE has accredited the process used by the Centre for Health Technology Evaluation ...»
Ranibizumab and pegaptanib for the
treatment of age-related macular
Issued: August 2008 last modified: May 2012
NICE technology appraisal guidance 155
NICE has accredited the process used by the Centre for Health Technology Evaluation at NICE to
produce technology appraisals guidance. Accreditation is valid for 5 years from September 2009 and
applies to guidance produced since June 2008 using the processes described in NICE's 'The guide to
the methods of technology appraisal' (2008). More information on accreditation can be viewed at www.nice.org.uk/accreditation © NICE 2008 Ranibizumab and pegaptanib for the treatment of age-related NICE technology appraisal macular degeneration guidance 155 Contents 1 Guidance
2 Clinical need and practice
3 The technologies
4 Evidence and interpretation
4.1 Clinical effectiveness
4.2 Cost effectiveness
4.3 Consideration of the evidence
6 Recommendations for further research
7 Related NICE guidance
8 Review of guidance
Appendix A: Appraisal Committee members and NICE project team
A Appraisal Committee members
B NICE project team
Appendix B: Sources of evidence considered by the Committee
Changes after publication
About this guidance
1 Guidance This guidance has been re-issued after a change to the patient access scheme in May 2012.
See About this guidance for more information.
1.1 Ranibizumab, within its marketing authorisation, is recommended as an option
for the treatment of wet age-related macular degeneration if:
1.2 It is recommended that treatment with ranibizumab should be continued only in people who maintain adequate response to therapy. Criteria for discontinuation should include persistent deterioration in visual acuity and identification of anatomical changes in the retina that indicate inadequate response to therapy.
It is recommended that a national protocol specifying criteria for discontinuation is developed.
1.3 Pegaptanib is not recommended for the treatment of wet age-related macular degeneration.
1.4 People who are currently receiving pegaptanib for any lesion type should have the option to continue therapy until they and their clinicians consider it appropriate to stop.
2 Clinical need and practice 2.1 Age-related macular degeneration (AMD) is an eye condition that leads to a progressive loss of central vision. People retain some peripheral vision, but the ability to see well enough to recognise faces, drive and read is affected, and vision can deteriorate rapidly.
2.2 AMD occurs in two forms, dry and wet AMD. Dry AMD (non-neovascular) is a form of extensive atrophy (wasting) of cells that progresses slowly, whereas the wet form can lead to a rapid worsening of vision. Wet (neovascular) AMD is characterised by the development of immature blood vessels that grow between the retinal pigment epithelial cells and the photoreceptor cells in the centre of the retina, a process known as choroidal neovascularisation (CNV).
These vessels easily haemorrhage and cause lesions on the macula, leading to visual impairment. A protein known as vascular endothelial growth factor (VEGF), which induces new blood vessel formation (angiogenesis), vascular permeability and inflammation, has been implicated in the development and progression of CNV. CNV can be subdivided into classic and occult forms according to its appearance on investigation by fluorescein angiography. A mixture of classic and occult CNV can occur in the same lesion. CNV can also be described in terms of its location: the fovea is the central part of the macula, and CNV that develops below the foveal area is termed 'subfoveal CNV'.
2.3 There are about 26,000 new cases of wet AMD in the UK each year and the condition affects more women than men. The condition usually affects people who are over 50 years old and the risk increases significantly with age. The most commonly cited risk factor for AMD is cigarette smoking; the risk of developing AMD is 3.6 times greater for current and former smokers than for people who have never smoked.
2.4 Patient management consists of social support, visual rehabilitation and the provision of aids to help with low vision. However, in the 20% of patients with classic no occult subfoveal CNV and a best-corrected visual acuity of 6/60 or better, photodynamic therapy (PDT) is an option. Visual acuity of 6/60 means that the patient can only see from a distance of 6 metres or less what someone with normal vision can see from 60 metres away. PDT involves injecting
verteporfin, a photosensitive drug that remains in the new blood vessels in the eye. This is followed by treatment with a low-powered laser, which activates the drug causing cell death. The aim is to destroy the CNV lesions without damaging the retina, thereby halting or reducing progressive loss of vision.
PDT does not prevent new vessels forming: it only treats established pathological vessels. More recently, drugs that inhibit the action of VEGF have been developed for the treatment of wet AMD.
3 The technologies Ranibizumab 3.1 Ranibizumab (Lucentis, Novartis) is a humanised therapeutic antibody fragment that binds to VEGF-A isoforms of VEGF thereby preventing binding of VEGF-A to receptors VEGFR-1 and VEGFR-2.
3.2 Ranibizumab has a UK marketing authorisation for the treatment of neovascular (wet) AMD. It is administered through intravitreal injection at a recommended dose of 0.5 mg. Treatment is started with a loading phase of one injection per month for 3 consecutive months, followed by a maintenance phase in which patients are monitored monthly for visual acuity. If the patient experiences a loss of greater than five letters in visual acuity (on the Early Treatment Diabetic Retinopathy Study [ETDRS] chart or one Snellen line equivalent) during this maintenance phase, a further dose of ranibizumab should be administered. The interval between two doses should not be shorter than 1 month.
3.3 The summary of product characteristics (SPC) states that adverse events commonly associated with ranibizumab include conjunctival haemorrhage, eye pain, vitreous floaters, retinal haemorrhage, increased intraocular pressure, vitreous detachment, intraocular inflammation, eye irritation, cataract, foreign body sensation in the eyes, visual disturbance, blepharitis, subretinal fibrosis, ocular hyperaemia, blurred/decreased visual acuity, dry eye and vitreitis. For full details of side effects and contraindications, see the SPC.
3.4 The cost of a ranibizumab injection is £761.20 (excluding VAT; British national formulary [BNF] 54th edition). The 2-year cost of ranibizumab is about £10,700 assuming 8 injections in the first year and 6 injections in the second year, and about £18,300 assuming 12 injections in the first year and another 12 in the second year as per clinical trial regimen. Costs may vary in different settings because of negotiated procurement discounts.
Pegaptanib 3.5 Pegaptanib (Macugen, Pfizer) is a pegylated modified oligonucleotide that binds to VEGF-165 and inhibits its activity.
3.6 Pegaptanib has a UK marketing authorisation for the treatment of neovascular (wet) AMD. It is administered at 0.3 mg once every 6 weeks (9 injections per year) by intravitreal injection into the affected eye.
3.7 The SPC states that adverse events commonly associated with pegaptanib are anterior chamber inflammation, eye pain, increased intraocular pressure, punctate keratitis, vitreous floaters and vitreous opacities. For full details of side effects and contraindications, see the SPC.
3.8 The cost of pegaptanib is £514.00 per injection (excluding VAT; BNF 52nd edition). The 2-year cost of pegaptanib is about £9,300 (9 injections in the first year and another 9 in the second year). Costs may vary in different settings because of negotiated procurement discounts.
4 Evidence and interpretation The Appraisal Committee (appendix A) considered evidence from a number of sources (appendix B).
4.1 Clinical effectiveness 4.1.1 The Assessment Group's systematic review identified four randomised controlled trials (RCTs) of ranibizumab and two RCTs of pegaptanib. Outcomes measured in the RCTs included changes in visual acuity (loss, maintenance, gain, mean change and deterioration to visual acuity 3/60 [in the UK, 3/60 is the level of visual acuity at which patients are registered blind]), anatomical changes in CNV lesions, visual function questionnaire scores, contrast sensitivity and adverse events.
4.1.2 Four RCTs of ranibizumab (MARINA [minimally classic lesions; ranibizumab versus sham injection], ANCHOR [predominantly classic lesions; ranibizumab versus sham plus PDT], PIER [all lesions; ranibizumab versus sham injection] and FOCUS [predominantly and minimally classic lesions; ranibizumab plus PDT versus sham plus PDT]) were included in the assessment report and the manufacturer's submission. The length of follow-up in the trials varied from 12 to 24 months and the doses used were 0.3 mg (unlicensed) and 0.5 mg (licensed). The populations in the trials met inclusion criteria including bestcorrected visual acuity between 6/12 and 6/96; no permanent structural damage to the central fovea; lesion size less than or equal to 12 disc areas in greatest linear dimension; and evidence of recent presumed disease progression (blood vessel growth as indicated by fluorescein angiography, or recent visual acuity changes). Outcomes were assessed at different time points, and the number and frequency of injections varied among the trials.
4.1.3 Loss of fewer than 15 letters of visual acuity was the primary endpoint in the studies. From baseline to 12 months, statistically significantly more patients receiving 0.5 mg ranibizumab lost fewer than 15 letters of visual acuity compared with both sham injection (94.6% compared with 62.2%, MARINA
study) and PDT (96.4% compared with 64.3%, ANCHOR study). In the PIER study, 90.2% of the 0.5 mg ranibizumab group lost fewer than 15 letters compared with 49.2% in the sham group (p 0.0001).
4.1.4 Gain in visual acuity was a secondary endpoint in the studies. A third of the
0.5 mg ranibizumab group gained at least 15 letters compared with 4% of the sham injection group at 24 months in the MARINA study. In the ANCHOR trial, 40% of the 0.5 mg ranibizumab group gained at least 15 letters compared with 6% of the PDT plus sham injection group (p 0.0001). In the FOCUS study, 24% of the 0.5 mg ranibizumab plus PDT group gained at least 15 letters compared with 5% of the sham injection plus PDT group (p = 0.0033).
4.1.5 The MARINA, ANCHOR and FOCUS trials all reported mean increases in visual acuity in the 0.5 mg ranibizumab group compared with baseline. The FOCUS trial reported mean gains in letters of 4.9 (0.5 mg ranibizumab plus PDT group) compared with mean losses of 8.2 letters in the sham plus PDT group. The ANCHOR study (0.5 mg ranibizumab group) reported mean gains of 11.3 letters compared with a loss of 9.5 letters in the sham plus PDT group.
In the MARINA trial, mean gains in letters were 7.2 and 6.6 at 12 and 24 months, respectively, and the corresponding mean losses in the sham group were 10.4 and 14.9 letters at 12 and 24 months respectively. These results were statistically significant in all the trials.
4.1.6 Most adverse events were mild to moderate. Conjunctival haemorrhage was the most widely reported eye-related adverse event, but its incidence varied among the ranibizumab RCTs and it was also common in the control groups.
More patients in the ranibizumab group experienced increased intraocular pressure and vitreous floaters compared with those in the sham injection group. Endophthalmitis affected about 1% and 0.7% of patients in the MARINA and ANCHOR RCTs respectively. The SPC stated that the overall incidence of arterial thromboembolic events from the MARINA, ANCHOR and PIER trials was higher for patients treated with ranibizumab 0.5 mg (2.5%) compared with the control arm (1.1%). However, in the second year of the MARINA study, the rate of arterial thromboembolic events was similar in patients treated with ranibizumab 0.5 mg (2.6%) compared with patients in the control arm (3.2%).
Pegaptanib 4.1.7 The combined results of two concurrent RCTs (one carried out in the USA and Canada, the other at centres worldwide) comparing doses of 0.3 mg (licensed),
1.0 mg (unlicensed) and 3.0 mg (unlicensed) pegaptanib with sham injection were published as the VISION study. A total of 1208 patients with all types of CNV lesion were included. Patients were followed for up to 54 weeks, then for a further 48 weeks after re-randomisation.
4.1.8 Loss of fewer than 15 letters of visual acuity was the primary endpoint in the VISION study. Statistically significantly more patients (70%) receiving 0.3 mg (the licensed dose) pegaptanib compared with sham injection (55%) lost fewer than 15 letters of visual acuity from baseline to 54 weeks. More patients in the
0.3 mg group gained at least five letters (22%) compared with the sham injection group (12%; p = 0.004). Gains of at least 10 letters were reported for 11% of the 0.3 mg pegaptanib group compared with 6% of the sham injection group (p = 0.02). In the 0.3 mg group 6% of patients gained more than 15 letters compared with 2% in the sham group.
4.1.9 Mean loss of letters of visual acuity at week 54 was significantly higher in the sham injection group than in the 0.3 mg pegaptanib group. A mean loss of 7.5 letters was observed in the 0.3 mg pegaptanib group, compared with a mean loss of 14.5 letters in the sham injection group.