To report the recent controversy surrounding the intraocular use of bevacizumab in India and its relationship to the broader problems of off-label drug use, medication compounding, and drug counterfeiting.
Data for this perspective were obtained from several sources. Literature reviews for compounding-related endophthalmitis and drug counterfeiting were performed. Supplemental information was obtained through targeted Google searches for related published manuscripts. First-hand accounts of negotiations between representatives of the Vitreoretinal Society of India (VRSI) and India’s Central Drugs Standards Control Organization (CDSCO) were provided by 2 of the authors (R.N., V.G.).
In December, 2015, 15 cases of intraocular inflammation following injections of counterfeit bevacizumab occurred in Gujarat, India. CDSCO reacted by prohibiting the use of intraocular bevacizumab throughout the country. Intense negotiations between the VRSI and CDSCO resulted in the permission to use bevacizumab in accordance with new safety guidelines. These include an enhanced informed consent process, the stamping of the Kezzler code on all bevacizumab vials, a real-time digital verification process between the end user and Roche Pharmaceuticals, and mandatory destruction of empty drug vials.
Counterfeit bevacizumab has caused outbreaks of sterile and infectious postinjection endophthalmitis in at least 3 countries during the past 5 years and has entered the supply chain in other countries. Physicians and compounding pharmacists need to be aware that international counterfeiters have targeted bevacizumab.
Once again, criminals have released counterfeit drugs into a country and patients have suffered. The drug in question is bevacizumab, which is legally manufactured by Genentech, S. San Francisco, California, USA/Roche, Basel, Switzerland. Back in 2010, Shanghai experienced an outbreak of sterile endophthalmitis following the injection of counterfeit bevacizumab into eyes of patients with exudative retinal diseases. The Chinese government immediately banned the use of bevacizumab, and even today its use is severely restricted in a country where there is a huge need for an inexpensive therapy to prevent blindness and many patients are unable to afford the approved drugs. This strategy simply does not make sense, given the evidence that bevacizumab is safe, effective, and as good as the more expensive therapies. After a similar outbreak in India, we waited to see if India was going to make the same mistake.
Bevacizumab (Avastin), a recombinant, humanized, full-length antibody that binds isoforms of vascular endothelial growth factor (VEGF), was developed and received approval for the intravenous treatment of colorectal carcinoma in 2004. Rather than develop bevacizumab for intraocular use, Genentech developed ranibizumab (Lucentis) for chorioretinal vascular conditions. While the phase III ranibizumab registration trials were ongoing, an equivalent dose of bevacizumab was shown to be effective when injected into eyes of patients with neovascular age-related macular degeneration (nAMD) and central retinal vein occlusion. The remarkable results from these single injections led to its rapid adoption throughout the world and made it the first-choice drug of most retina specialists. Subsequent multicenter, randomized clinical trials validated its effectiveness in patients with nAMD and diabetic macular edema (DME).
Bevacizumab is also used to treat vascular conditions for which intraocular anti-VEGF drugs have not been approved. These conditions include inflammatory-related choroidal neovascularization, myopic choroidal neovascularization, proliferative diabetic retinopathy in eyes without macular edema, neovascular glaucoma, and retinopathy of prematurity. Registration trials for ranibizumab and aflibercept (Eylea) have not been conducted for these conditions and intraocular anti-VEGF use is not approved in children because they were excluded from all of the pivotal trials. Since anti-VEGF treatment of each of these clinical scenarios is considered off-label, drug costs are generally not reimbursed by health care systems and insurance companies. Bevacizumab is therefore used extensively in these scenarios and represents an affordable choice compared to ranibizumab and aflibercept (respective unit dose for nAMD: $60 vs $1950 vs $1850). Unfortunately, many regulatory bodies and legal systems frown upon off-label drug use, including intraocular bevacizumab, and restrict its use in some countries, most notably China.
Anti-VEGF drug availability throughout the world depends not only on cost but also on approvals granted by regulatory authorities and coverage provided by private insurance companies. Drugs are usually approved by each country’s health care agencies, so there is a great deal of variability in the availability of anti-VEGF drugs throughout the world. In some countries, insurance companies have instituted policies that are contrary to those of the regulatory authorities by requiring that physicians always begin anti-VEGF therapy with bevacizumab and allow switching to a more expensive drug only after petitioning the insurer (usually because of an incomplete response or adverse reaction). In other countries, governments refuse to allow off-label use of bevacizumab; such is the case in China. France recently allowed physicians to use bevacizumab to treat patients with nAMD, and in response, the European Federation of Pharmaceutical Industries and Associations filed a complaint with the European Commission stating that France “… introduced legislation that not only contradicts EU law, but also puts the overall EU regulatory system aimed at guaranteeing the highest patient safety standards at risk.” The global use of bevacizumab has strained the relationship between government regulatory bodies, industry, insurers and payers, and physicians because its off-label use (which is unquestionably effective and safe) has deprived the pharmaceutical companies of billions of dollars of revenue. Conversely, governments and insurance companies throughout the world have saved billions of dollars from the use of bevacizumab. Thus, there is a struggle between what is right for patients and what is right for industry, with government agencies caught in the middle trying decide what is fair, appropriate, and safe for their citizens.
Insurance companies and health systems of industrialized countries provide reimbursement for the drug chosen by the treating physician, but in developing countries cost often dictates drug selection. Underfunded national health systems may choose not to pay for expensive drugs. The single-dose cost of bevacizumab in India may be as high as $60, but it still remains affordable for a proportion of the population when compared to ranibizumab ($300 in India).
Compounding of bevacizumab has been a major safety concern since the first reports of intravitreal use. Several outbreaks of compounding-related endophthalmitis have been reported in the United States and Canada in patients receiving bevacizumab. In almost all cases, the endophthalmitis outbreak occurred because of breakdown in sterile technique owing to failure to follow United States Pharmacopeia Chapter 797 guidelines. These outbreaks, together with clusters of infections attributable to the inappropriate compounding of other medications, prompted state and federal governments to aggressively enforce existing laws and pass new legislation to ensure high-quality compounding. Whereas the risk of endophthalmitis attributable to compounded bevacizumab was a concern in the past, recent reports suggest that the overall incidence of endophthalmitis may be lower with bevacizumab than with either ranibizumab or aflibercept. This might reflect the fact that the repackaging of bevacizumab involves its dispensation in a prefilled sterile syringe, thus avoiding the task of having to withdraw the drug from vials in a nonsterile environment, as is the case with ranibizumab and aflibercept.
The sterility of compounded bevacizumab has not been the only issue complicating its use in ophthalmology. Counterfeit bevacizumab has surfaced in several countries. Bevacizumab is the seventh-highest-grossing drug worldwide ($6.8 billion in 2014 sales) and has become a target of international counterfeiters. In 2010, 116 patients received counterfeit bevacizumab from 3 vials in Shanghai, and 80 developed intraocular inflammation. Twenty patients underwent vitrectomy for severe inflammation and all 80 patients eventually returned to preinjection visual acuities. None of the patients was diagnosed with microbial endophthalmitis. In 2012, 2 batches of fake bevacizumab were sold to 76 US physicians’ offices in 22 states by a distributing pharmacy named Canada Drugs. To secure a low-cost supply of bevacizumab, the pharmacy purchased fake (labeled as manufactured by Roche and not Genentech) drug from foreign suppliers through the “gray market” (defined as a secondary wholesale market outside of the traditional primary sourcing chain), in violation of the US Food, Drug and Cosmetic Act. Drugs flowed through a complex network of wholesalers in several countries, including Turkey, Switzerland, Denmark, the UK, and Canada, before finally arriving in US clinics. The fake bevacizumab in this case contained corn starch, acetone, and other compounds, none of which had antiangiogenesis properties. This became the first documented case of counterfeit cancer drugs sold to US physicians for administration in an office setting.
Despite the ongoing FDA investigation into counterfeit bevacizumab penetrating the US market, Ban Dune Marketing sold a fake version of bevacizumab labeled with the Turkish brand name, “Altuzan,” to a group of US doctors in 2013. Following this event, some 1000 warning letters were sent by the FDA to physicians’ practices and hospitals in 48 states. Distributors were forced to stop selling drugs to US physicians and at least 11 criminal proceedings were brought against the principals. Even after 4 years of investigations into this matter, the details surrounding entry of these products into the supply chain and the extent of patient harm remain unclear. According to Ronald Noble, secretary-general of the international police organization Interpol, “The Avastin case was a watershed moment for law enforcement to recognize that this is not a problem that can be restricted to one part of the world. It let the US know it’s not immune to [counterfeit drugs].”
In 2013, researchers in Mexico cultured Scytalidium sp from an unused vial of bevacizumab that had been contaminated before it was opened. Additional analysis showed that the vial contained 3% polyethylene glycol, citrate, and ethanol, but no bevacizumab. The vial’s seal lacked proper identification and the label, batch number, and expiration date did not correspond to that of genuine bevacizumab.
A cluster of 15 post-bevacizumab endophthalmitis cases from a single vial of bevacizumab occurred in Gujarat, India in December 2015. The packaging on the vial appeared authentic, but analysis of its contents found microbial contamination and no evidence of bevacizumab. As a result, on January 21, 2016 India’s Central Drugs Standards Control Organization (CDSCO) took the bold step of prohibiting the use of intraocular bevacizumab. Unfortunately, CDSCO’s decision to protect patients from a small group of criminals passing counterfeit bevacizumab put a large portion of the population at risk of blindness from exudative and neovascular eye diseases. Because much of the Indian population is unable to purchase the more expensive ranibizumab, many patients diagnosed with these diseases will not be treated. And there is no guarantee that drugs with marketing approval will not be counterfeited. The problem is not with the drugs, the problem is with the criminals who create and distribute any counterfeit drug, market approved or otherwise.
Negotiations between members of the Vitreoretinal Society of India (VRSI) and CDSCO ensued in an attempt to reinstate bevacizumab for off-label use while also ensuring security of the supply chain. After 2 weeks, CDSCO agreed to allow retinal surgeons to use bevacizumab after they obtain informed consent from patients specifying its off-label use. Roche has been directed to reintroduce the Kezzler code (advanced digital mass encryption technology) for every vial to minimize the chance of counterfeit drug entering the supply chain. The end user must send the code by text SMS to Roche, which will then verify the authenticity of the bevacizumab vial. Members of the VRSI have been directed to destroy bevacizumab vials after use because it is believed that counterfeiters have previously used discarded vials to repackage counterfeit drug. Roche has also been asked to provide a list of authorized dealers and distributors from which practices can purchase bevacizumab.
As of this writing, the reversal order by CDSCO had been finalized and members of VRSI were once again able to use bevacizumab. Roche has agreed to cooperate with this plan to secure the bevacizumab supply chain, but did not agree to 2 additional points: they would not provide single-dose aliquoted volumes of bevacizumab to distributors or physicians, and they would not recommend bevacizumab for intraocular use. Unlike the outcome following the use of counterfeit bevacizumab in China, this thoughtful decision by CDSCO will significantly benefit the patients of India, as more patients will be able to afford the vision-saving anti-VEGF therapy that they need.
Entry of counterfeit drugs into the supply chain has been recognized by the World Health Organization since 1988, but despite problems with bevacizumab, antimalarial drugs, erythropoietin, rituximab, oxaliplatin, zoledronic acid, gemcitabine, and pegfilgrastim, no concerted effort to secure the international supply chain has been undertaken. Preventing future entry of counterfeit drugs into the supply chain will not be easy because of the large number of manufacturers, shippers, distributors, and compounding pharmacies involved in bevacizumab production and distribution. It will require a concerted effort between these concerned organizations and possibly even law enforcement agencies. Global surveillance is needed to counter the dangers associated with counterfeit drugs, and until industry voluntarily reintroduces the Kezzler code on all pharmaceuticals it is the responsibility of health care professionals to ensure that their drugs are purchased from reliable suppliers and that they immediately report any suspicions of counterfeit drugs to the appropriate authorities. It is essential that we punish the criminals responsible for manufacturing and distributing counterfeit drugs, not the patients.