|Year : 2019 | Volume
| Issue : 6 | Page : 377-383
Bevacizumab for eye diseases – Legal, regulatory, and ethical overview
Vinu Jose, Swetha Radhakrishna, Parag Pipalava, Inderjeet Singh
Clinical Development and Medical Affairs, Intas Pharmaceuticals Ltd. (Biopharma), Ahmedabad, Gujarat, India
|Date of Submission||14-Jul-2019|
|Date of Decision||12-Sep-2019|
|Date of Acceptance||23-Dec-2019|
|Date of Web Publication||16-Jan-2020|
Dr. Vinu Jose
Intas Pharmaceuticals Ltd. (Biopharma), Moraiya, Ahmedabad, Gujarat
Source of Support: None, Conflict of Interest: None
Vascular endothelial growth factor (VEGF) inhibitors, ranibizumab, aflibercept, and pegaptanib are approved treatments for certain eye diseases that occurs especially in the elderly. These drugs are mostly inaccessible due to their high cost. Bevacizumab is a VEGF inhibitor, approved for cancer treatment. Being a cheaper alternative, it is extensively used off-label as an intravitreal injection for the treatment of eye diseases. In this article, we have analyzed similarities and differences between bevacizumab and ranibizumab, and potential long-term safety concerns with off-label use of bevacizumab. We also analyzed legal, regulatory, and ethical background of off-label use and provided recommendations to resolve this issue. Based on the extensive clinical data, actions taken, and recommendations provided by agencies such as the National Institute for Health and Care Excellence, International Council of Ophthalmology, United Kingdom and Thailand regulatory agency, intravitreal bevacizumab has adequate evidence for controlled licensing. Claiming better safety for ranibizumab at the expense of nonaffordability cannot be considered a positive risk-benefit scenario. Intravitreal bevacizumab is being used and will continue to be used off-label, if not regulatory controlled. Licensing will ensure the availability of intravitreal bevacizumab to the patients with eye diseases, without any legal or ethical concerns for the clinicians, and will also assist in generating long-term safety data. Safest delivery formulation and dosage form should be considered for approval. Both the regulatory agency and technical experts should join and take critical decision, which will be a big step forward to making a cost-effective drug available to the public.
Keywords: Bevacizumab, eye disease, intravitreal, off-label, ranibizumab
|How to cite this article:|
Jose V, Radhakrishna S, Pipalava P, Singh I. Bevacizumab for eye diseases – Legal, regulatory, and ethical overview. Indian J Pharmacol 2019;51:377-83
|How to cite this URL:|
Jose V, Radhakrishna S, Pipalava P, Singh I. Bevacizumab for eye diseases – Legal, regulatory, and ethical overview. Indian J Pharmacol [serial online] 2019 [cited 2020 Aug 15];51:377-83. Available from: http://www.ijp-online.com/text.asp?2019/51/6/377/276045
| » Introduction|| |
Ranibizumab, an inhibitor of vascular endothelial growth factor (VEGF), is a monoclonal antibody which is approved for use in certain eye diseases with VEGF involvement [Table 1]. Due to the high prevalence of these eye diseases, especially in the elderly, and the exorbitant cost of ranibizumab, alternative drugs are used and at times misused. New drugs such as aflibercept and pegaptanib, which also inhibit VEGF, have been approved for eye diseases with VEGF involvement,, but are largely inaccessible due to their high cost., A few other VEGF inhibitors, such as bevacizumab, ramucirumab, and zivaflibercept are also approved for use, but in cancers. However, bevacizumab is extensively used off-label as an intravitreal injection for the treatment of such eye diseases.
|Table 1: Differences between Bevacizumab and Ranibizumab (per approved labels)|
Click here to view
In this article, we have compared bevacizumab and ranibizumab - clinical trials conducted were compared; legal, regulatory, and ethical background surrounding the present situation analyzed; policies taken by a few agencies and countries presented and potential long-term safety concerns identified and presented. Finally, we have provided recommendations to bring justice to the needy patients in a developing country like India.
| » Comparison of Bevacizumab With Ranibizumab|| |
Bevacizumab is a monoclonal antibody approved for use as intravenous infusion in certain types of cancers, while ranibizumab is a monoclonal antibody approved as intravitreal injection for certain eye diseases., Both bevacizumab and ranibizumab bind to VEGF and prevent the interaction between VEGF and its receptors, thereby reducing the proliferation of endothelial cells and formation of new blood vessels., Differences between bevacizumab and ranibizumab are presented in [Table 1].
| » Clinical Studies of Intravitreal Bevacizumab|| |
Multiple clinical studies have been conducted with intravitreal bevacizumab, comparing it with ranibizumab and aflibercept, in terms of efficacy and safety in various eye diseases.
A meta-analysis of eight randomized controlled trials (RCTs) conducted globally in 3140 neovascular age-related macular degeneration patients (AMD) showed similar efficacy for bevacizumab and ranibizumab with respect to best-corrected visual acuity (BCVA) at 2 years. However, ranibizumab reduced central macular thickness (CMT) more at 1 year. Similar rates of the incidence of arteriothrombotic events, death, or venous thrombotic events were noted with bevacizumab and ranibizumab at 1 and 2 years; however, significantly higher rates of serious systemic adverse events were noted with bevacizumab at 1 and 2 years.
A meta-analysis of three clinical studies in 117 patients with myopic choroidal neovascularization concluded that intravitreal bevacizumab and ranibizumab showed similar improvement in visual acuity. The safety profile was also similar between bevacizumab and ranibizumab.
A meta-analysis of eight RCTs in 394 patients (414 eyes) with proliferative diabetic retinopathy showed that bevacizumab as adjuvant intravitreal injection before vitrectomy significantly made the procedure easy and decreased complications during operation and post operation period without increasing complications.
A meta-analysis of 11 RCTs in 1830 patients with macular edema following retinal vein occlusion showed no significant differences between bevacizumab, ranibizumab, and aflibercept in efficacy (BCVA improvement and CMT reduction) and safety profiles.
A meta-analysis compared aflibercept, bevacizumab, and ranibizumab with respect to effectiveness and safety. A total of 24 RCTs (6007 patients) were included, of which 14 studies were conducted with ranibizumab (1518 eye), eight studies with bevacizumab (515 eyes), and three studies with aflibercept (975 eyes). The analysis showed that aflibercept may provide some advantage in terms of visual and anatomic outcomes over bevacizumab and ranibizumab at 1 year, but it is unclear whether these findings can be extrapolated to the long-term efficacy. The safety profile was similar between the three drugs.
Overall, meta-analyses of multiple clinical studies conducted with intravitreal bevacizumab have shown that bevacizumab is not inferior to standard treatments, including ranibizumab, for efficacy and safety, in various eye diseases. Since human exposure data already exist, animal study data published from academic sources were ignored since it does not improve the interpretation value – animal studies are considered as checkpoints before human use. No regulatory submission studies could be identified that were conducted in India with permission from drug controller general of India (DCGI) by any pharmaceutical companies for comparing intravitreal bevacizumab with intravitreal ranibizumab.
| » Global Legal and Regulatory Framework for Off-Label Use|| |
If a drug, available in a market following approval for a particular indication, is used for another unapproved disease or medical condition, such situation is commonly termed off-label use of medication by the United States Food and Drug Administration (US FDA). The use of a particular medicine in an age group for which it is not approved, or at dosages for which it is not approved or via a route for which it is not approved, is called off-label use as per the European Medicines Agency (EMA). The Drugs and Cosmetics Act of India has not clearly defined off-label use in India; however, the concept is the same as in the US and Europe. Since the innovator company has not submitted data for the approval of bevacizumab in eye diseases, regulators have not approved its intravitreal use, because of which use of bevacizumab in eye diseases falls under the purview of “off-label” use. The reason for such a stance taken by the innovator is beyond the scope of this article.
The manner in which off-label use of a drug is regulated in different countries differs. The rules are quite liberal in Japan, where off-label use is allowed even without submitting any preliminary clinical data. No laws in the US or Canada prohibits off-label drug use. FDA promotes studies in pediatric patients, giving the manufacturers an additional 6-month exclusivity. EMA takes a supportive stand on drugs that has crossed patent, especially for clinical studies in off-label indications in children. The Swiss federal law allows the temporary regulatory exemption, under exceptional conditions (such as life-threatening conditions), when a greater therapeutic benefit can be expected from the off-label use and no alternative treatment is available. The French law also allows temporary off-label use, restricted to 3 years; the pharmaceutical company has to monitor the off-label use and report it to an expert committee, which can decide whether to continue or withdraw the off-label use. In contrast, the Indian regulatory agency does not regulate medical practice or prescription of drugs for off-label uses. In general, the decision to prescribe off-label drugs is left with expert clinician. Under the Drugs and Magic Remedies (Objectionable Advertisements) Act, 1954 of India, off-label marketing by pharmaceutical companies is considered as an offense. These laws are meant to restrict illegal use of drugs; however, it limits (and does not motivate) the scope for improvement in therapy based on evidence. Hence, the use and promotion of intravitreal bevacizumab create a confusing situation for clinicians where there is no clarity whether it is legally punishable in situations of serious adverse events since regulations of the country do not approve the use of intravitreal bevacizumab. Regulatory control over generalized off-label use of drugs is a controversial area on its own and is beyond the scope of this article.
Bevacizumab (Avastin ®, Genentech, Inc.) initially got approved for colorectal cancer in the US by the FDA; however, the visual acuity and anatomical improvement observed by Rosenfeld when bevacizumab was used to treat AMD in the year 2005 led to the widespread use of off-label bevacizumab for AMD. Bevacizumab is now widely used globally for visual impairment due to retinal diseases, in spite of the availability of ranibizumab.
The innovator has neither tested bevacizumab for eye diseases either in animals or in humans nor requested for approval in eye diseases; hence, the innovator cannot be held liable for the safety of intravitreal bevacizumab use. Hence, national regulatory agencies are in a dilemma in approving intravitreal bevacizumab and are also unable to track the off-label use-related safety. This leaves the national agencies with limited options, such as taking up the responsibility of developing it on their own or enforcing the innovator to develop it, or an option of a hybrid plan to support an interested company to develop it. A decision on this front is an immediate necessity since lack of action by the national agency is leading to a helpless situation for needy patients, i.e., nonaccessibility to the approved treatments due to high burden of cost as well as the lack of an organized safety database for intravitreal bevacizumab.
| » Ethical Concerns and Off Label Use|| |
Dictionaries define ethics as “moral principles that govern a person's behavior or the conducting of an activity.” or “a system of accepted beliefs that control behavior, especially such a system based on morals.”, The medical ethics which relies on autonomy, justice, beneficence and non-maleficence is challenged in situations where a clinician rejects treatment to a patient when the availability of bevacizumab with “sufficient” safety generated from patients' exposure exists and the patient is unable to receive other approved treatments due to high cost. From a common man's perspective too, when an accessible and effective treatment option is denied to a patient, there is an ethical challenge in accepting it. Claiming better safety of ranibizumab at the expense of non-affordability cannot be considered a positive risk-benefit scenario.
Off-label use is a balance between ethics and legal/regulatory status. Drugs are developed to improve the quality of life of humankind. Pharmaceutical companies thrive on the profit generated by drugs, but if the fundamental requirements of patients are not fulfilled, the entire drug development cannot be justified. Prescription of an off-label drug should be considered ethical when the drug is cost-effective, patient cannot afford another approved drug, and enough safety data exist.
It is well known that bevacizumab is cost-effective as compared with ranibizumab. In India, a single-use vial of ranibizumab costs around INR 17,500–71,000; a single-use vial of aflibercept costs around INR 56,700; and bevacizumab 100 mg/4 mL vial costs around INR 28,000. As the required ophthalmic use dose of bevacizumab is 1.25 mg, up to 10–18 doses of bevacizumab can be prepared from a single 100 mg vial, costing INR 1000–2000 per dose, which is 30–50 times cheaper than ranibizumab. These calculations assume the stable cost of ranibizumab.
The current situation jeopardizes national regulatory agencies from legal, regulatory, and ethical perspective due to the unavailability of an interested pharmaceutical company to develop intravitreal bevacizumab. There are instances where certain countries or agencies have looked at the present legal, regulatory, and ethical situation and taken a positive stance based on already available safety data.
| » The Thailand Paradigm|| |
Visual impairment secondary to AMD and diabetic macular edema (DME) is common in the elderly population of Thailand. Majority of the patients cannot afford ranibizumab due to its high cost (54,000 baht/dose). In 2011, the Thai Ministry on request from the National List of Essential Medicines (NLEM) compared the efficacy and safety of bevacizumab with ranibizumab for AMD and DME. The study concluded similar efficacy between bevacizumab and ranibizumab; however, the safety of bevacizumab was inconclusive. Based on these findings, the subcommittee suggested that ranibizumab should be the drug of choice if the producer reduces the price; however as the discussion to reduce the price failed, the committee endorsed the ophthalmic use of bevacizumab and listed bevacizumab in the NLEM for use in AMD and DME. In addition, the committee suggested the establishment of a national registry for monitoring the drug's effectiveness and safety. Sangroongruangsri et al. compared the real-world safety of intravitreal bevacizumab with intravitreal ranibizumab in patients in Thailand and concluded that there were no major safety concerns with intravitreal bevacizumab and ranibizumab.
| » International Agencies' Support for Off-Label Use of Bevacizumab|| |
A workshop held by National Institute for Health and Care Excellence (NICE) on 13 July 2010 concluded that: There is support for an appraisal of intravitreal bevacizumab for eye conditions. Stakeholders agreed that an appraisal would need to be conditional on, or incorporate the assessment of, the safety and quality of intravitreal bevacizumab by a regulatory body or through the involvement of regulatory expertise. It was suggested that options for commissioning the relevant skills and expertise for this purpose be explored. Arrangements for safety monitoring/pharmacovigilance will need to be explored.
The United Kingdom (UK) legislation allows manufacturing and supplying of “specials” (also known as unlicensed medicinal products) based on the following three conditions: (1) there is a bona fide unsolicited order for the same, (2) the drug is formulated per the requirement of a registered doctor, and (3) the drug is for use under doctor's direct personal responsibility for patients. Documentation should be maintained, and serious adverse events reported to the health authority. Based on these rules, two major pharmacies supply intravitreal bevacizumab: Liverpool and Broadgreen University Hospitals pharmacy and Moorfields Pharmaceuticals which manufactures for Moorfields Eye Hospital NHS Foundation Trust. The storage stability of this newly formulated preparation has been proven.
The International Council of Ophthalmology had suggested that bevacizumab should be added to the World Health Organization's existing list of essential eye medicines for use in developing countries.
Twelve Clinical Commissioning Groups from the North of England adopted a policy, to offer intravitreal bevacizumab to certain patients as the preferred treatment. The policy was challenged by the claimants but was dismissed by the court. There was evidence that intravitreal bevacizumab has a proven market, is extensively available in the UK and elsewhere, and hence, it is lawful for treating physicians to choose bevacizumab. The court also referred to the NICE guideline to conclude that bevacizumab is safe.
| » Clinical Safety and Pharmacovigilance|| |
Clinical studies of up to 2 years duration with intravitreal bevacizumab have shown no major safety concerns.,,,, Safety issues may occur due to faulty drug preparation and administration techniques. The dose of bevacizumab (1.25 mg) required for ophthalmic use is much lower than the dose required for cancer (5–15 mg/kg). Therefore, smaller aliquots have to be prepared from the available 4 mL or 16 mL vials for ophthalmic use. This technique of splitting into smaller doses has to be done under aseptic conditions with extreme precautions; otherwise, this can increase the risk of infections. Cases of endophthalmitis have been reported with intravitreal bevacizumab. Aseptic preparation technique can be followed in a clinical trial setup; however, for large scale production and in the Indian setup, this could be cumbersome. Therefore, the ideal case will be to develop a single-dose, new strength of bevacizumab for intravitreal administration by a pharmaceutical company itself, considering the safety and regulatory implications.
The dose of intravitreal bevacizumab (1.25 mg) is 150–400 times less than the dose used in cancer (5–15 mg/kg), and therefore, it is unlikely that intravitreal bevacizumab would cause any serious systemic adverse events. However, available evidence from clinical studies demonstrates a possible systemic exposure with intravitreal bevacizumab. In the CATT study, slightly increased rate of systemic adverse events which were of serious nature were noted with bevacizumab than with ranibizumab at 1 and 2 years., Both bevacizumab and ranibizumab have a different systemic half-life, and hence, their systemic effects are also different. A pharmacokinetic/pharmacodynamic analysis study showed notable differences in the systemic pharmacokinetics between bevacizumab and ranibizumab. Bevacizumab had proportionally higher systemic levels and lower VEGF levels. There was an association noted between the decrease in free VEGF levels and increase in circulating anti-VEGF agents. In the IVAN study, the concentration of VEGF was significantly lower with bevacizumab than with ranibizumab at 1 year. The longer eye half-life (5.5 days) and slow release from eye to the systemic blood because of the larger size is the possible explanation. This probably is the reason for the biological effects observed in the contralateral eye after the intravitreal administration of bevacizumab.
The major problem with off-label use is the lack of long-term safety data. The treatment duration in the majority of clinical studies with intravitreal bevacizumab was 2 years or less, and patient exposure was also limited,,,,, because of which it is unsure if there could be safety concerns with the long-term use. Hence, intravitreal bevacizumab should be strictly monitored for safety and it should have a long-term surveillance period, which will ensure a reliable safety and efficacy database for this “unofficial” widely used drug. Patients with AMD are treated for many years and hence, it is important to demonstrate safety beyond 2 years.
In general, both physicians and drug manufacturers should strictly monitor off-label use. Physicians have the responsibility to inform the patient adequately about the off-label use; if not, the physician can be liable to legal consequences, not necessarily on medical negligence. Considering the present legal, regulatory and ethical situation, availability of up to 2 years of safety and efficacy data, the lead taken by certain agencies and countries in recommending usage, it is the right time for the national regulatory agency to proceed with approval of single-use intravitreal bevacizumab formulation with the commitment for long-term safety monitoring.
| » Conclusion and Recommendations|| |
Based on the extensive clinical study data, actions taken by certain regulatory agencies, and recommendations by different agencies, intravitreal bevacizumab has enough evidence for controlled licensing. A single usage dosage form should be the choice for approval. Licensing should ensure immediate availability of intravitreal bevacizumab to the patients and generation of an organized long-term exposure safety database, without any legal and ethical concerns for the clinicians.
Financial support and sponsorship
Intas Pharmaceuticals Ltd. India supported publication of this article. There was no financial support provided.
Conflicts of interest
The authors are employees of Intas Pharmaceuticals Ltd., India. Intas has manufacturing and marketing approval in India for bevacizumab for oncology indication as well as ranibizumab for eye indications.
| » References|| |
van Asten F, Michels CT, Hoyng CB, van der Wilt GJ, Klevering BJ, Rovers MM, et al
. The cost-effectiveness of bevacizumab, ranibizumab and aflibercept for the treatment of age-related macular degeneration-A cost-effectiveness analysis from a societal perspective. PLoS One 2018;13:e0197670.
Azad R, Chandra P, Gupta R. The economic implications of the use of anti-vascular endothelial growth factor drugs in age-related macular degeneration. Indian J Ophthalmol 2007;55:441-3.
] [Full text]
Saif MW. Anti-VEGF agents in metastatic colorectal cancer (mCRC): Are they all alike? Cancer Manag Res 2013;5:103-15.
Gunther JB, Altaweel MM. Bevacizumab (Avastin) for the treatment of ocular disease. Surv Ophthalmol 2009;54:372-400.
Nguyen CL, Oh LJ, Wong E, Wei J, Chilov M. Anti-vascular endothelial growth factor for neovascular age-related macular degeneration: A meta-analysis of randomized controlled trials. BMC Ophthalmol 2018;18:130.
Loutfi M, Siddiqui MR, Dhedhi A, Kamal A. A systematic review and meta-analysis comparing intravitreal ranibizumab with bevacizumab for the treatment of myopic choroidal neovascularisation. Saudi J Ophthalmol 2015;29:147-55.
Zhang ZH, Liu HY, Hernandez-Da Mota SE, Romano MR, Falavarjani KG, Ahmadieh H, et al
. Vitrectomy with or without preoperative intravitreal bevacizumab for proliferative diabetic retinopathy: A meta-analysis of randomized controlled trials. Am J Ophthalmol 2013;156:106-15.e2.
Sangroongruangsri S, Ratanapakorn T, Wu O, Anothaisintawee T, Chaikledkaew U. Comparative efficacy of bevacizumab, ranibizumab, and aflibercept for treatment of macular edema secondary to retinal vein occlusion: A systematic review and network meta-analysis. Expert Rev Clin Pharmacol 2018;11:903-16.
Virgili G, Parravano M, Evans JR, Gordon I, Lucenteforte E. Anti-vascular endothelial growth factor for diabetic macular oedema: A network meta-analysis. Cochrane Database Syst Rev 2018;10:CD007419.
Office of the Commissioner. Understanding Unapproved Use of Approved Drugs “Off Label”. Food and Drug Administration; 2019. Available from: http://www.fda.gov/patients/learn-about-expanded-access-and-other-treatment-options/understanding-unapproved-use-approved-drugs-label. [Last accessed on 2019 Jun 17].
Oberoi SS. Regulating off-label drug use in India: The arena for concern. Perspect Clin Res 2015;6:129-33.
] [Full text]
Zheng Z, Yang M, Wu J. Ethical off-label drug use: Need for a rethink? Indian Pediatr 2017;54:447-50.
Lenk C, Duttge G. Ethical and legal framework and regulation for off-label use: European perspective. Ther Clin Risk Manag 2014;10:537-46.
Emmerich J, Dumarcet N, Lorence A. France's new framework for regulating off-label drug use. N Engl J Med 2012;367:1279-81.
Gota V, Divatia JV. Off-label use of drugs: An evil or a necessity? Indian J Anaesth 2015;59:767-8.
] [Full text]
Rosenfeld PJ, Moshfeghi AA, Puliafito CA. Optical coherence tomography findings after an intravitreal injection of bevacizumab (avastin) for neovascular age-related macular degeneration. Ophthalmic Surg Lasers Imaging 2005;36:331-5.
Dakin HA, Wordsworth S, Rogers CA, Abangma G, Raftery J, Harding SP, et al
. Cost-effectiveness of ranibizumab and bevacizumab for age-related macular degeneration: 2-year findings from the IVAN randomised trial. BMJ Open 2014;4:e005094.
Kumar A, Tripathy K, Chawla R. Intraocular use of bevacizumab in India: An issue resolved? Natl Med J India 2017;30:345-7.
] [Full text]
Anothaisintawee T, Leelahavarong P, Ratanapakorn T, Teerawattananon Y. The use of comparative effectiveness research to inform policy decisions on the inclusion of bevacizumab for the treatment of macular diseases in Thailand's pharmaceutical benefit package. Clinicoecon Outcomes Res 2012;4:361-74.
Sangroongruangsri S, Chaikledkaew U, Kumluang S, Wu O, Geue C, Ratanapakorn T, et al
. Real-World Safety of Intravitreal Bevacizumab and Ranibizumab Treatments for Retinal Diseases in Thailand: A Prospective Observational Study. Clin Drug Investig 2018;38:853-65.
Poku E, Rathbone J, Everson-Hock E, Essat M, Wong R, Pandor A, et al
. Bevacizumab in Eye Conditions: Issues Related to Quality, Use, Efficacy and Safety. Decision Support Unit; 2012.
Khalili H, Sharma G, Froome A, Khaw PT, Brocchini S. Storage stability of bevacizumab in polycarbonate and polypropylene syringes. Eye (Lond) 2015;29:820-7.
Media Summary. Bayer Plc and Novartis Pharmaceuticals UK Ltd v Various Clinical Commissioning Groups; 2018. Available from: Ttps://www.judiciary.uk/wp-content/uploads/2018/09/bayer-and-novartis-v-nhs-darlington-ccg-summary.pdf. [Last accessed on 2019 Jun 30].
Khan P, Khan L, Mondal P. Cluster endophthalmitis following multiple intravitreal bevacizumab injections from a single use vial. Indian J Ophthalmol 2016;64:694-6.
] [Full text]
CATT Research Group, Martin DF, Maguire MG, Ying GS, Grunwald JE, Fine SL, et al
. Ranibizumab and bevacizumab for neovascular age-related macular degeneration. N Engl J Med 2011;364:1897-908.
Comparison of Age-related Macular Degeneration Treatments Trials (CATT) Research Group, Martin DF, Maguire MG, Fine SL, Ying GS, Jaffe GJ, et al
. Ranibizumab and bevacizumab for treatment of neovascular age-related macular degeneration: Two-year results. Ophthalmology 2012;119:1388-98.
Avery RL, Castellarin AA, Steinle NC, Dhoot DS, Pieramici DJ, See R, et al
. Systemic pharmacokinetics and pharmacodynamics of intravitreal aflibercept, bevacizumab, and ranibizumab. Retina 2017;37:1847-58.
IVAN Study Investigators, Chakravarthy U, Harding SP, Rogers CA, Downes SM, Lotery AJ, et al
. Ranibizumab versus bevacizumab to treat neovascular age-related macular degeneration: One-year findings from the IVAN randomized trial. Ophthalmology 2012;119:1399-411.
Grisanti S, Ziemssen F. Bevacizumab: Off-label use in ophthalmology. Indian J Ophthalmol 2007;55:417-20.
] [Full text]
Hanhart J, Tiosano L, Averbukh E, Banin E, Hemo I, Chowers I, et al
. Fellow eye effect of unilateral intravitreal bevacizumab injection in eyes with diabetic macular edema. Eye (Lond) 2014;28:646-53.