The Controversies Surrounding Bevacizumab and Ranibizumab

Age-related macular degeneration (AMD) is a leading cause of visual impairment and blindness. Both bevacizumab and ranibizumab are anti-vascular endothelial growth factors used for treatment of AMD. However the use of bevacizumab remains controversial as it was not approved for intravitreal use although there were several head-to-head comparison trial that shows that it was non inferior to ranibizumab. Despite the status of off-label, intravitreal bevacizumab is being used worldwide as it is 30-50 times cheaper than intravitreal ranibizumab. The case of intravitreal bevacizumab illustrates the use of “not-me” drug and different countries responds differently to its use.


INTRODUCTION
Age-related macular degeneration (AMD) affects those 50 years and older and causes 1% of visual impairment and 5% of blindness globally [1]. Both bevacizumab (brand name Avastin®) and ranibizumab (brand name Lucentis®) are being use for AMD by ophthalmologists worldwide. However, the intravitreal use of bevacizumab for AMD remains controversial as Opinion Article the use remains off-label. As described by Jansen [2], "the bevacizumab-ranibizumab debacle illustrates the ethical, policy and legal dilemmas encountered with the off-label use of medication".

CHRONOLOGY OF REGISTRATION OF BEVACIZUMAB AND RANIBIZUMAB
Both bevacizumab and ranibizumab, an antivascular endothelial growth factor (VEGF) were developed by Genentech, which was acquired by Roche in 2009. Ranibizumab is marketed by Novartis outside USA. Bevacizumab is a humanised full-length antibody that is derived from the same monoclonal antibody as ranibizumab. Therefore it is likely to recognise the same epitope on all isoforms of VEGF as ranibizumab, but having a different binding affinity. Bevacizumab was first approved by FDA for intravenous use in metastatic colon cancer in 2004 [3]. Ophthalmologist had started using bevacizumab when there were case reports on its efficacy. The obvious efficacy resulted in the rapid adoption in many countries. Ranibizumab was later approved for intravitreal use by FDA for treatment of patients with neovascular (wet) AMD in 2006 [4]. The use of bevacizumab for AMD continues after ranibizumab approval as the price of bevacizumab is 30-50 times cheaper than ranibizumab and more evidence showed the relative efficacy and safety of bevacizumab to ranibizumab. Lack of incentive of marketingintravitreal bevacizumab for AMD use might deter the company for registering the drug for AMD use. All CATT, IVAN, GEFAL and MANTA trials were designed as multicentre, prospective and randomised control trial yet the non-inferiority limit for all 4 trials differs slightly. The primary outcome studied was best-corrected visual acuity (BCVA). MANTA trial was powered to detect a difference of 7 letters with 95% confidence, more letters than CATT (5 letters with 99.2% confidence), GEFAL (5 letters with 95% confidence) and IVAN (3.5 letters with 95% confidence). The results from all 4 trials shows that bevacizumab was non-inferior to ranibizumab (Table 1).

RESULTS OF LATEST PUBLISHED META-ANALYSIS COMPARING INTRAVITREAL BEVACIZUMAB TO INTRAVIREAL RANIBIZUMAB
In addition to the head-to-head trial, there were several systemic reviews and meta-analysis which showed intravitreal bevacizumab was non inferior to intravitreal ranibizumab in terms of efficacy [11][12][13]. In terms of safety aspect, it was found that bevacizumab tends to have higher risk of adverse effects as shown in meta-analysis by Wu et al. [11] and the risk of serious systemic events increased by 17% (95% CI 6%-27%, P = 0.0042) for bevacizumab treatment in comparison with ranibizumab. Another metaanalysis conducted by Kodjikian et al. [12] found that bevacizumab was associated with a 34% increase in the number of patients with at least one serious systemic adverse event (OR 1.34, 1.08 to 1.66, P = 0.01, I 2 = 0 %). The result was consistent with another meta-analysis conducted by Chen et al which found increase risk of systemic adverse events with bevacizumab [pooled risk ratios comparing the rates of serious systemic adverse events at 1 year and 2 years were slightly in favour of ranibizumab (risk ratio = 1.24, 95% CI, 1.04-1.48, P = 0.02 and risk ratio = 1.20, 95% CI, 1.05-1.37, P = 0.008, respectively)], whereas the rates of death, arteriothrombotic events and venous thrombotic events did not differ statistically [13].

Royal Society of OphthalmologyUK [14]
Based on the latest guidelines issued by the Royal Society of Ophthalmology, UK in 2013 [14], bevacizumab was having similar functional efficacy as ranibizumab. However its unlicensed use for intraocular purpose need to be highlighted and its prescriber need to convey the "off-label" status to the patient prior to its administration to patient. It was also mentioned in the guidelines that for the licensed anti-VEGF treatment, further research is required into appropriate duration and optimal regimen in terms of frequency of injections as there is lack of evidence on whether less frequent dosing of licensed treatment will achieve the same visual benefit as those in pivotal trials.

American Academy of Ophthalmology [15]
American Academy of Ophthalmology recommend the use of both bevacizumab and ranibizumab for age-related macular degeneration.
For bevacizumab, the ophthalmologist need to obtain the informed consent from the patient with regards to its offlabel use.

Malaysia
At the present moment, only ranibizumab is listed in the Ministry of Health Drug Formulary (as of 07/07/2014) for AMD in the public sector. There was evidence of usage of intravitreal bevacizumab in Malaysia but the extent and indication of its use is unknown.

United Kingdom
There were mixed reaction in terms of usage of bevacizumab in the UK. The NHS North East Treatment Advisory Group (NETAG) reported that there will be a significant cost saving of using bevacizumab and the efficacy for both bevacizumab and ranibizumab is comparable.
Hence, bevacizumab was used in NHS North East treatment centres [21]. From the economic analysis conducted by the NETAG, the use of six doses of ranibizumab in the first year will cost £4.766 million per annum. If bevacizumab was used instead the cost would be £274,200, a saving of £4.491 million [21]. If the result of CATT was applied where 1 extra injection was required per annum for bevacizumab, the cost of using bevacizumab is still £4.007 million less than using ranibizumab [21]. On the other hand, the south coast of England (Southampton, Hampshire, Isle of Wight and Portsmouth) cluster of primary care trust discontinued the policy funding of bevacizumab as an alternative treatment for wet AMD after Novartis seek judicial review of the decision [22,23].

Italy
Recently, the Italian antitrust authorities had fined the two Swiss pharmaceutical companies, Novartis and Roche for a total of $250 million for "colluding to keep doctors from prescribing a relatively inexpensive drug" [24]. The authorities claimed that "the two companies had sought to steer doctors away from Avastin as had been use as off-label for years to channel demand toward the much more expensive Lucentis, through an artificial distinction between the two products by overstating the dangers of Avastin use" [24]. The Italian authority estimated that the addition cost of €45million in 2012 to Italian health service was due to the collusion and this cost might exceed €600m a year in the future [24].

Thailand
The

CONCLUSION
Based on evidence from head-to-head trials comparing bevacizumab and ranibizumab for AMD, it was found that bevacizumab was noninferior to ranibizumab in terms of efficacy. However, some studies shows that the use of bevacizumab was associated with an increased risk of developing serious systemic events as compared to ranibizumab. The widespread use of bevacizumab despite its offlabel status is due to the significant difference of cost between the two drugs as ranibizumab is 30-50 times more expensive than bevacizumab. Selection of either agents depends on the country viewpoint in terms of public health needs and priority. When cost is the main concern, the country will opt for cheaper yet "off-label" bevacizumab. However, due to legal implication of off-label use, some countries will prefer to choose the drug with licensed indication. If a physician need to prescribe the intravitreal bevacizumab, the "off-label" status of the drug should be conveyed to the patient.