An application was submitted by the International Council of Ophthalmology for the inclusion of bevacizumab for the treatment of proliferative (neovascular) eye diseases.
Expert reviews were provided by Dr Gitanjali Batmanabane, Dr Abdol Majid Cheraghali and Dr Nicola Magrini. The application was supported by the Prevention of Blindness and Deafness unit, WHO.
Age-related macular degeneration (AMD) is the leading cause of blindness in persons over 50 years of age in developed countries. It is estimated that by 2020 as many as 7.5 million people worldwide over the age of 65 years may have vision loss attributable to this disease (220). Between 10% and 20% of patients with AMD are expected to have the neovascular form of AMD which is responsible for 90% of all cases of severe vision loss. The Expert Committee consequently accepted that there is a clear public health need for the treatment of neovascular AMD.
The application for bevacizumab was based on a large, randomized, controlled trial – the Comparison of AMD Treatments Trials (CATT) funded by the National Institutes of Health, USA – which compared bevacizumab with ranibizumab (221, 222). The trial randomized 1200 patients to one of four treatments: either bevacizumab or ranibizumab and either monthly or “as needed” treatment regimens. For the primary outcome of change in visual acuity at one and two years of follow-up, bevacizumab and ranibizumab were equivalent. Bevacizumab administered monthly was equivalent to ranibizumab administered monthly, with 8.0 and 8.5 letters gained on the visual acuity scores, respectively. Bevacizumab administered as needed was equivalent to ranibizumab as needed, with 5.9 and 6.8 letters gained, respectively.
The analysis of adverse outcomes showed that rates of death, myocardial infarction and stroke were similar for patients receiving either bevacizumab or ranibizumab. The Expert Committee also considered the hospitalization events with bevacizumab compared with ranibizumab (24.1% versus 19.0%; RR: 1.29, 95% CI: 1.01–1.66), and noted that the excess events were broadly distributed in disease categories that had not been identified in previous studies. The Committee accepted the explanation given in the study that the differences in hospitalization rates were probably due to baseline imbalances. The Committee also noted that in the trial the higher doses of bevacizumab (monthly regimen) were associated
with a lower hospitalization rate than the lower dose (“as needed” regimen), which might be explained by chance or by baseline imbalances in the groups for comorbidities or other patient characteristics.
The Expert Committee also considered the results from a second trial
that was not mentioned in the application. This British study (IVAN)6 with
300 patients per arm was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme (223). The results of the trial showed that the two treatments had similar efficacy and safety, including comparisons of monthly versus “as needed” treatment regimens. In the IVAN trial systemic arteriothrombotic events and heart failure were less frequent for bevacizumab than for ranibizumab (0.7% versus 2.9%, OR: 0.23, 95% CI: 0.05–1.07, P = 0.03).
The Expert Committee considered the observational studies evaluating the safety of bevacizumab, or comparing bevacizumab and ranibizumab. These data were mostly from record-linkage studies or large pharmacoepidemiology databases. The European Medicines Agency report of July 2012 which reviewed all these safety studies of bevacizumab concluded that: “… the CHMP agreed that detailed safety information provided from the CATT and IVAN studies is reassuring and no evidence can be provided that bevacizumab is systemically more unsafe than ranibizumab and vice-versa. The CATT study was not powered to detect rare adverse events or to show differences in the number of events with a relatively high background incidence in elderly people with AMD” (224).
The Expert Committee noted that currently available formulations of bevacizumab are not specifically formulated for intravitreal injections. Bevacizumab comes in a sterile solution of 25 mg/ml (i.e. 1.25 mg per 0.05 ml) so it does not need to be diluted, reconstituted or altered in any way. The Committee considered that reports of adverse events (e.g. endophthalmitis) resulting from reformulation of the vial size currently available for use for multiple injections had been traced to inadequate sterility in the compounding process. The Committee noted, therefore, that safe use of bevacizumab as currently formulated requires that use may need to be restricted to a single patient per vial, notwithstanding the wastage. Any alternative approach to using a single vial for multiple patients would have to comply with appropriate safe and sterile injection practices, including any requirements for storage of the product, to ensure that there would be no possibility of contamination. However, even allowing for wastage, on the basis of anecdotal cost comparisons the cost of using currently available vials of bevacizumab for intravitreal injection may be less than one-twentieth of the cost of using alternative products such as ranibizumab.
6 A randomized controlled trial of alternative treatments to inhibit vascular endothelial growth factor
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The Expert Committee concluded that, on the basis of the head-to-head comparative trials and the observational safety data, intraocular bevacizumab is effective and safe for the treatment of neovascular AMD.
While noting the absence of stringent regulatory authority approval for the use of bevacizumab for the indication of AMD, the Expert Committee recommended that it be included in the EML on grounds of public health need, demonstrated safety and effectiveness, and favourable cost–effectiveness. The Committee again drew attention to the need for safe preparation and administration of intravitreal bevacizumab. The Committee recommended the listing of bevacizumab 25 mg/ml injection (100-mg vial) in the complementary list in a new Section 21.6 on anti-vascular endothelial growth factor (VEGF) preparations.