ranibizumab, 10mg/mL solution for injection (Lucentis ) SMC No. (711/11) Novartis Pharmaceuticals UK Ltd

Transcription

1 ranibizumab, 10mg/mL solution for injection (Lucentis ) SMC No. (711/11) Novartis Pharmaceuticals UK Ltd 10 June 2011 The Scottish Medicines Consortium (SMC) has completed its assessment of the above product and advises NHS Boards and Area Drug and Therapeutic Committees (ADTCs) on its use in NHS Scotland. The advice is summarised as follows: ADVICE: following a full submission ranibizumab (Lucentis ) is not recommended for use within NHS Scotland. Indication under review: Treatment of visual impairment due to diabetic macular oedema in adults. Ranibizumab significantly improved visual acuity over 12 months compared with standard laser photocoagulation treatment. The manufacturer s justification of the treatment s health benefits in relation to its cost was not sufficient and in addition, the manufacturer did not present a sufficiently robust economic analysis to gain acceptance by SMC. The licence holder has indicated their intention to resubmit. Overleaf is the detailed advice on this product. Chairman, Scottish Medicines Consortium Published 11 July

2 Indication Ranibizumab is indicated for the treatment of visual impairment due to diabetic macular oedema (DMO) in adults. There is some experience of ranibizumab administered concomitantly with laser photocoagulation and it can be administered in patients who have received previous laser photocoagulation. Dosing Information Ranibizumab 0.5mg is administered as a single intravitreal injection. Treatment is given monthly and continued until maximum visual acuity is achieved i.e the patient's visual acuity is stable for three consecutive monthly assessments performed while on ranibizumab treatment. If there is no improvement in visual acuity over the course of three injections, continued treatment is not recommended. Thereafter patients should be monitored monthly for visual acuity. Treatment is resumed when monitoring indicates loss of visual acuity due to DMO. Monthly injections should then be administered until stable visual acuity is reached again for three consecutive monthly assessments (implying a minimum of two injections). The interval between two doses should not be shorter than one month. There is some experience of ranibizumab administered concomitantly with laser photocoagulation. When given on the same day, ranibizumab should be administered at least 30 minutes after laser photocoagulation. Ranibizumab can be administered in patients who have received previous laser photocoagulation. Ranibizumab must be administered by a qualified ophthalmologist experienced in intravitreal injections. Product availability date January 2011 Summary of evidence on comparative efficacy Diabetic macular oedema (DMO) is swelling of the central part of the retina, the macula, which mediates high-resolution visual acuity. DMO is caused by the breakdown of the blood retinal barrier leading to leakage of fluid and plasma. If left untreated DMO causes loss of visual acuity equivalent to at least two lines (early treatment diabetic retinopathy study [ETDRS] 10 letters) within 2 years in approximately 50% of patients. Ranibizumab is a humanised recombinant monoclonal antibody fragment that inhibits the binding of vascular endothelial growth factor A (VEGF-A) to its receptors thereby preventing endothelial cell proliferation, neovascularisation and vascular leakage, which are all thought to be contributing factors in the progression of DMO. Evidence supporting this submission is from two phase III studies comparing ranibizumab with the current standard treatment, laser photocoagulation, (hereafter referred to as laser). The pivotal 12 month, randomised, double-masked study recruited 345 adult patients with type 1 or type 2 diabetes mellitus; HbA1c 10.0%; on diet, exercise, and/or diabetic medication 2

3 which was stable for the previous three months; with visual impairment due to focal or diffuse DMO; best corrected visual acuity (BCVA) 78 to 39 ETDRS letters. Only one eye was treated and if both eyes were eligible the worse seeing eye was treated unless the investigator decided that the better seeing eye was more appropriate. After screening, patients were randomly assigned (1:1:1) to: intravitreal ranibizumab 0.5mg monotherapy, laser monotherapy or a combination of both treatments. Masking was achieved using sham intravitreal injections and sham laser treatment. Intravitreal ranibizumab/sham injection was administered once a month for three months initially. If stable vision was not reached, monthly injections continued until vision was stabilised (no further improvement) or reached > 84 letters (approximately 20/20 Snellen equivalent) for two visits and then stopped. Assessments continued every month and treatment was re-started if there was a decrease in BCVA due, in the opinion of the investigator, to progression of DMO. Treatment was at monthly intervals until stable vision was reached again at two consecutive visits, i.e. restarting of intravitreal injections comprised at least two injections. Laser treatment (active or sham) was administered at baseline and then as required according to the ETDRS protocol at intervals of at least three months. The mean number of ranibizumab injections/sham received was similar for all treatment groups (6.8 to 7.3 injections) and the mean number of active/sham laser administrations was similar for all treatment groups (1.7 to 2.1 administrations). Laser treatment for DMO in the fellow eye was permitted. The primary outcome was mean average change from baseline of BCVA letter score over all monthly post-baseline assessments from month 1 to month 12. The primary analysis was performed on the full analysis set, i.e. all patients who received any study treatment and had at least one post-baseline assessment for BCVA. Missing data were imputed using the last observation carried forward (LOCF) approach but the missing values occurring between observed values were replaced by the mean of the adjacent observations (before and after) to the missing time-point. Significant improvements in mean average BCVA change for month 1 to month 12 from baseline were achieved with ranibizumab monotherapy (+6.1 letters standard deviation [SD] 6.4), and ranibizumab plus laser combination therapy (+5.9 letters SD 7.9), compared with laser alone (+0.8 letters SD 8.6). Treatment difference versus laser in least squares mean values were 5.3 (95% confidence interval [CI]: 3.5 to 7.3) for ranibizumab monotherapy and 4.9 (95% CI: 2.8 to 7.0) for ranibizumab plus laser. Ranibizumab produced clinically significant improvements in visual acuity in more patients than laser alone. The proportion of patients experiencing a gain in BCVA of 2 lines (10 letters) or more was 37% in the ranibizumab monotherapy group, 43% in the ranibizumab plus laser combination therapy group and 16% in the laser monotherapy group. Nearly a quarter (23%) of ranibizumab-treated patients (± laser) gained at least 3 lines (15 letters), compared with 8% of patients treated with laser alone. However in 56% of patients the change was less noticeable, ranging between a deterioration of 10 letters and an improvement of 10 letters. Subgroup analysis of 68 ranibizumab-treated patients with retinal ischaemia at baseline (moderate capillary loss to completely destroyed capillaries in the centre subfield) found no indication of a reduced treatment effect (mean average change from baseline 6.3 letters) compared with patients with no baseline retinal ischaemia (mean average change from baseline 5.9 to 7.2 letters). There were no statistically significant differences in the European Quality of Life EQ-5D mean scores over time. Vision-related quality of life functioning was measured using the NEI VFQ-25 questionnaire in which a five-point change in the NEI VFQ-25 subscales and a four-point change in composite score are considered as small clinically meaningful differences. After 12 3

4 months, the mean improvement from baseline in the NEI VFQ-25 composite score was significantly greater in patients treated with ranibizumab monotherapy (5.0 points) or ranibizumab plus laser combination therapy (5.4 points) than in patients treated with laser alone (0.6 points). Ranibizumab monotherapy and ranibizumab plus laser combination therapy provided significant improvements on the general vision, near activities and distance activities subscales compared with laser alone. A supportive, randomised, double-masked study evaluated laser photocoagulation or ranibizumab plus prompt laser (within 3 to 10 days after injection) or ranibizumab plus deferred laser ( 24 weeks from study entry) or triamcinolone plus prompt laser for DMO. The study included 691 patients 18 years with type 1 or type 2 diabetes mellitus; BCVA 24 to 78 electronic ETDRS letters; definite retinal thickening due to DMO involving the centre of the macula and assessed as the main cause of visual loss; retinal thickness 250 micrometres in the central subfield. If eligible, both eyes were treated, comprising a total of 854 study eyes. Patients with one study eye were assigned randomly, stratified by study eye visual acuity, with equal probability to one of the four treatment groups. For participants with two eligible study eyes, the right eye was assigned randomly among the four groups. If the right eye was assigned to any drug intervention, then the left eye was assigned to sham injection plus laser treatment. If the right eye was assigned to sham injection plus laser treatment, then the left eye was randomly assigned to any of the three drug intervention groups at equal probabilities. There were therefore more eyes in the sham injection plus prompt laser group than in the other three groups: sham intravitreal injection plus prompt laser (n=293, where n = number of study eyes), ranibizumab 0.5mg intravitreal injection plus prompt laser (n=187), ranibizumab 0.5mg intravitreal injection plus deferred laser (n=188) or triamcinolone 4mg intravitreal injection plus prompt laser (n=186). Visits were every four weeks and treatment with ranibizumab/sham was administered at the first four visits. At week 16, if either success or failure criteria were met, treatment with ranibizumab/sham was stopped. Retreatment was according to an algorithm and at the investigator s discretion. Laser treatments had to be at least 13 weeks apart. For the deferred laser treatment group, laser could not be given until the six-month visit, after which the retreatment algorithm indicated treatment need. Patients in the three laser groups were masked to treatment assignment till the primary outcome visit, however the ranibizumab plus deferred laser group was not masked. The ranibizumab groups had a median of eight to nine injections over the year. The primary outcome was mean change in visual acuity from baseline to one year using the intention to treat principle for all randomised eyes. Missing values were imputed using LOCF. The primary analysis compared each drug intervention group with the prompt laser plus sham injection group. Significantly larger mean improvements in BCVA from baseline to month 12 were achieved with ranibizumab plus laser combination therapy (+9 letters with either prompt or deferred laser; SD 11 and 12 respectively) than laser alone (+3 letters SD 13). The triamcinolone plus laser group result was [+4 SD 13]). The estimated treatment difference between 0.5mg ranibizumab plus prompt laser and sham injection plus laser treatment groups was 5.8 letters (95% CI: 3.2 to 8.5). The estimated treatment difference between 0.5mg ranibizumab plus deferred laser and sham injection plus laser treatment groups was 6.0 letters (95% CI: 3.4 to 8.6). The proportions of patients who achieved at least 10 letters improvement in BCVA were 47% (88/188) for ranibizumab plus deferred laser, 51% (95/187) for ranibizumab plus prompt laser, 28% (81/293) for laser and 33% (61/186) for triamcinolone plus prompt laser. 4

5 Summary of evidence on comparative safety In the pivotal study a similar proportion of patients in each treatment group experienced ocular adverse events (AE) in the study eye; ranibizumab monotherapy (43%), ranibizumab plus laser combination therapy (43%), and laser alone (39%). The most common ocular AEs in the ranibizumab groups were eye pain, conjunctival hyperaemia, conjunctival haemorrhage and foreign body sensation. The incidence of ocular serious adverse events (SAEs) was low and none were considered to be treatment-related. Non-ocular AEs were experienced by a similar proportion of patients in each treatment group; ranibizumab monotherapy (58%), ranibizumab plus laser combination therapy (46%), and laser alone (62%). The most common were nasopharyngitis and hypertension. Few of the nonocular AEs were suspected to be related to study drug, ranibizumab monotherapy (5.2%), ranibizumab plus laser combination therapy (0.8%) or laser alone (1.8%). Non-ocular SAEs (all cause) were more frequent in the ranibizumab monotherapy group (20%), than in the ranibizumab plus laser combination therapy (14%) or laser monotherapy (14%) groups. Three patients in the ranibizumab monotherapy group and one patient in the ranibizumab plus laser combination therapy group had a cardiovascular or cerebrovascular AE. In the supportive study there was a low incidence of major ocular AEs with ranibizumab plus laser combination therapy, similar to that of laser alone. There were reports of retinal vein occlusion (1 each in the laser and the two ranibizumab groups, 3 in the triamcinolone group), increased intraocular pressure (similar in the ranibizumab and laser groups, 6 to 9% and 42% in the triamcinolone group) and 3 reports of endophthalmitis (ranibizumab patients). There were no systemic AEs over two years, however the study was not powered to detect this outcome. Evidence on safety in patients with DMO is short-term and limited especially with respect to less common adverse events, long-term treatment and combination use with laser photocoagulation. The number of retreatment injections required and the duration of continuing treatment are unknown. The DMO population is substantially younger than the wet age-related macular degeneration (AMD) population (in which ranibizumab is currently used) and potential complications after repeated long-term intravitreal injections of ranibizumab are unknown. There is a potential risk of arterial thromboembolic events following intravitreal use of VEGF inhibitors especially in diabetic patients who are already at increased risk of thrombosis. The risk of systemic absorption in patients with DMO is increased due to greater permeability of the eyes, and therefore there is a potentially higher risk of hypersensitivity reactions compared with the wet AMD population. Summary of clinical effectiveness issues Ranibizumab is the first medicine licensed to treat DMO. It significantly improved visual acuity over 12 months compared with standard laser photocoagulation. The submitting company has presented a cost-effectiveness case for ranibizumab when used in adults with visual impairment due to DMO with BCVA 75 ETDRS letters and with treatment only for the better seeing eye. In the clinical studies, however, the worse seeing eye was 5

6 generally treated and some patients with milder vision loss were included. The company acknowledges, however, that acceptability to patients and clinicians of restricting ranibizumab treatment to the better seeing eye is an important consideration and suggests that SMC recommendations should not necessarily be limited to treatment of the better seeing eye. Although ranibizumab has been compared with laser, the aims of these treatments differ. Laser treatment preserves but does not improve visual acuity. There is a substantial group of patients who are unresponsive to laser treatment, eg those with macular ischaemia or generalised oedema. Long term, repeated laser treatment may reduce vision by damaging large parts of the retina. There are several uncertainties associated with the use of ranibizumab. In over half the patients in the pivotal study the change in BCVA was small, ranging between a deterioration of 10 letters and an improvement of 10 letters. There is insufficient robust evidence of the efficacy (persistence of effect) and safety of ranibizumab beyond one year. The number of retreatment injections and the duration of continuing treatment are unknown. The supportive study described above reported a need to monitor eyes continually as additional ranibizumab and/or laser treatment was required in most eyes for at least two years. There is evidence of a small clinically significant improvement in quality of life for ranibizumab compared with laser treatment. The DMO population is substantially younger than the wet AMD population and potential complications after repeated long-term intravitreal injections of ranibizumab are unknown. It is not known if the short-term benefits of ranibizumab may be outweighed over time by a detrimental effect on vision preservation caused by stopping or deferring laser photocoagulation. Ranibizumab may be administered alone or in combination with laser photocoagulation although combination therapy has not demonstrated additional treatment benefit and evidence is lacking concerning its long-term effectiveness. Currently patients with DMO may be treated with laser even if they have no visual loss. Ranibizumab treatment is licensed only for patients with impaired vision due to DMO. The European Medicines Agency (EMA) expects that, prior to impairment of vision, DMO would be treated with laser photocoagulation with initiation of ranibizumab treatment when vision deteriorates. SMC experts have advised that there is some use of unlicensed intravitreal bevacizumab to treat DMO in NHS Scotland. The National Institute for Health and Clinical Excellence (NICE) has been asked to consider the feasibility of undertaking an appraisal of the clinical and costeffectiveness of intravitreal bevacizumab in eye conditions. Ranibizumab must be injected under aseptic conditions. Patients should self-administer antimicrobial drops for three days before and after each injection and should be monitored during the week following the injection to permit early treatment if an infection occurs. The EMA notes that due to the major risks of incorrect injection procedure, there will be a need for a continuous education of physicians in this field. The requirement for monthly monitoring visits, while receiving ranibizumab treatment and also after its discontinuation to determine need for retreatment, may have substantial implications for the service. 6

7 Summary of comparative health economic evidence The economic case relates to the use of ranibizumab in adults with visual impairment due to DMO with BCVA 75 ETDRS letters and with treatment only for the better seeing eye. The modelling approach to treating only the better seeing eye, reflects that taken within the NICE TA155 appraisal of ranibizumab in age-related macular degeneration. NICE concluded that its considerations of cost-effectiveness should relate to starting treatment with the first eye to present clinically. These recommendations have been approved by NHS Quality Improvement Scotland as valid for NHS Scotland. The manufacturer presented a 15 year cost-utility markov model with a 3 monthly cycle of ranibizumab monotherapy compared to laser monotherapy. Eight health states were defined by BCVA in the treated eye. The model was restricted to only those with a BCVA of 75 letters in the treated eye receiving treatment. It was assumed that the treated eye was at baseline the better seeing eye, and remained the better seeing eye for the duration of the model. Given this assumption, patient quality of life and whether the patient fell into severe visual impairment was determined solely by the BCVA in the treated eye. The transition probabilities for the first year were drawn from the pivotal study, with the transition probabilities for the second year being informed by the supportive study which suggested equal proportions of 2.5% improving and worsening in each cycle for ranibizumab and laser. Thereafter, informed by Wisconsin epidemiologic study of diabetic retinopathy (WESDR) data, there was a general average worsening assumed with 2.5% improving and 3.5% worsening per cycle. Quality of life values were taken from an EQ-5D study of UK patients with diabetic retinopathy, the values relating to each patient s overall BCVA. Dosing was drawn from the pivotal and supporting studies, with the number of ranibizumab injections being 7 in the first year and 3 in the second. An additional 2 injections were assumed to be required in both year three and year four. The annual numbers of laser treatments were taken to be 2, 1, 1 and 1 for years one, two, three and four respectively. The costs of severe visual impairment were estimated from a standard reference within the literature, with some adjustment for the diabetic population under consideration. Additional costs were associated with adverse events while on treatment, the rates of these being drawn from the pivotal study. The manufacturer proposed a patient access scheme (PAS) that offered a simple discount on the list price of ranibizumab. The PAS was accepted by the Patient Access Scheme Assessment Group (PASAG) therefore it was considered by SMC as part of the health economic case. As SMC has not recommended use of the medicine, however, the PAS cannot be implemented in NHS Scotland 7

8 The economic analysis based on the PAS resulted in base case estimates of a net patient gain of 0.23 quality adjusted life years (QALYs) and a net cost of 7,342 to yield a cost effectiveness estimate of 31,840 per QALY. Results were sensitive to the time horizon, the required number of ranibizumab injections, the costs of severe visual impairment, the relative risk of mortality for patients with DMO, the patient age at baseline and the source of the utility values applied. There were a number of weaknesses in the analysis: The analysis assumed that only the better seeing eye would be treated with ranibizumab but SMC clinical experts advised that this is not how ranibizumab would be used in clinical practice; While there was no presentation of cost-effectiveness results in relation to treating the worse seeing eye, it is likely that cost-effectiveness would be poorer as there would be lower levels of quality of life gains, which are pivotal to driving the results; The analysis assumed that the treated eye remained the better seeing eye over the period of the model which meant that both the patient quality of life and the cost savings from reduced rates of severe visual impairment were solely determined by the BCVA in the treated eye; The analysis included a cost of 150 for administration of the treatment, based on NHS reference costs. Sensitivity analysis showed that if this figure was increased to 274, the cost per QALY increased to 36,285. SMC clinical experts suggested that the NHS in Scotland does not currently have capacity to deliver the treatment. The cost of administration used in the base case may therefore underestimate the true marginal cost of using ranibizumab in practice and the sensitivity analysis shows that the results are sensitive to this parameter.. The results were sensitive to the number of injections used. SMC clinical experts suggested that as the patient population may be relatively young, there is the potential that more injections will be given than assumed in the base case. Sensitivity analysis showed that the results were sensitive to this aspect; if 18 injections of ranibizumab were used over a 6 year time period, the ICER rose to 41,778 per QALY. Given these weaknesses, in addition to the comparatively high incremental cost per QALY, the economic case was not demonstrated. Other data were also assessed but remain commercially confidential.* Summary of patient and public involvement Patient Interest Group Submissions were received from: Diabetes UK Scotland RNIB Scotland Additional information: guidelines and protocols The Scottish Intercollegiate Guidelines Network published (SIGN) 116 Management of diabetes in March This recommends that modified ETDRS grid laser photocoagulation should be used for patients with clinically significant macular oedema in the absence of significant macular ischaemia. 8

9 The Royal College of Ophthalmologists Preferred Practice Guidance Diabetic Retinopathy Screening (DRS) and the Ophthalmology Clinic set up in England September 2010 Laser photocoagulation is the standard of care for diabetic maculopathy and proliferative retinopathy. It is shown that timely, appropriate laser treatment can reduce the risk of vision loss in these patients by 50%. Evidence of new treatment options for both diabetic maculopathy and proliferative diabetic retinopathy is gathering pace. Intravitreal therapy, using steroid preparations as well as anti-vegf agents is increasingly finding its way in clinical practice. Currently no licensed products are available for diabetic retinopathy per se, however, clinical use of intravitreal triamcinolone, dexamethasone, bevacizumab, pegaptanib and ranibizumab have been shown to be promising. It is therefore important that the hospital eye service considers implications of such treatment options in the care of DR patients and services are planned so as to accommodate such therapeutic advances. Additional information: comparators The relevant comparator is laser photocoagulation. Bevacizumab is also being used to treat DMO however this use is unlicensed. Cost of relevant comparators Drug Dose Regimen Cost per year ( )* Ranibizumab 0.5mg intravitreally every month until maximum visual acuity is achieved. When monitoring indicates loss of visual acuity due to DMO monthly injections should be resumed until stable visual acuity is reached again for three consecutive monthly assessments (implying a minimum of two injections). 5,328 Cost from MIMS February 2011 * Annual cost based on mean of seven injections used in pivotal study 9

10 Additional information: budget impact The manufacturer estimated that 138 patients would be treated with ranibizumab in year 1 and 622 patients in year 5, based on 5% uptake in eligible patients in year 1 and 15% in year 5. Without implementation of the PAS, the manufacturer estimated a gross drug cost of 357k in year 1, rising to 1.6m in year 5. The overall net cost including administration costs was estimated as 500k in year 1 rising to 2.2m by year 5. The manufacturer assumed that the service implications associated with introducing ranibizumab in the treatment of diabetic macular oedema would be minimal but this is not borne out by advice from SMC clinical experts. 10

11 References The undernoted references were supplied with the submission. Novartis Clinical study report CRFB002D2301A randomized, double-masked, multicenter, laser controlled Phase III study assessing the efficacy and safety of ranibizumab (intravitreal injections) as adjunctive and mono-therapy in patients with visual impairment due to diabetic macular edema (RESTORE) 07/05/2010 Elman MJ, Aiello LP, Beck RW et al. for the Diabetic Retinopathy Clinical Research Network. Randomized trial evaluating ranibizumab plus prompt or deferred laser or triamcinolone plus prompt laser for diabetic macular edema. Ophthalmology 2010; 117: The European Medicines Agency (EMA) European Public Assessment Report for Ranibizumab (Lucentis ) 21/10/2010, EMEA/H/C/000715/II/ *Agreement between the Association of the British Pharmaceutical Industry (ABPI) and the SMC on guidelines for the release of company data into the public domain during a health technology appraisal: This assessment is based on data submitted by the applicant company up to and including 13 May Drug prices are those available at the time the papers were issued to SMC for consideration. These have been confirmed from the evadis drug database. SMC is aware that for some hospital-only products national or local contracts may be in place for comparator products that can significantly reduce the acquisition cost to Health Boards. These contract prices are commercial in confidence and cannot be put in the public domain, including via the SMC Detailed Advice Document. Area Drug and Therapeutics Committees and NHS Boards are therefore asked to consider contract pricing when reviewing advice on medicines accepted by SMC. Patient access schemes: A patient access scheme is a scheme proposed by a pharmaceutical company in order to improve the cost-effectiveness of a drug and enable patients to receive access to cost-effective innovative medicines. A Patient Access Scheme Assessment Group (PASAG, established under the auspices of NHS National Services Scotland reviews and advises NHS Scotland on the feasibility of proposed schemes for implementation. The PASAG operates separately from SMC in order to maintain the integrity and independence of the assessment process of the SMC. When SMC accepts a medicine for use in NHS Scotland on the basis of a patient access scheme that has been considered feasible by PASAG, a set of guidance notes on the operation of the scheme will be circulated to Area Drug and Therapeutics Committees and NHS Boards prior to publication of SMC advice. 11

12 Advice context: No part of this advice may be used without the whole of the advice being quoted in full. This advice represents the view of the Scottish Medicines Consortium and was arrived at after careful consideration and evaluation of the available evidence. It is provided to inform the considerations of Area Drug & Therapeutics Committees and NHS Boards in Scotland in determining medicines for local use or local formulary inclusion. This advice does not override the individual responsibility of health professionals to make decisions in the exercise of their clinical judgement in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer. 12