In 2010, a medical “ethics crisis” was sparked by the sensational “Ophthalmologygate” incident in Shanghai, which focused on a drug called Avastin. Six months later, the article “Ranibizumab and Bevacizumab for Neovascular Age-Related Macular Degeneration” in the April 28 online edition of the New England Journal of Medicine (NEJM) has again attracted attention. The article, “Lanivasumab and Bevacizumab for Neovascular Age-Related Macular Degeneration,” in the April 28 online edition of NEJM, has once again attracted attention and sparked a revisiting of the “ophthalmologygate” story. So, what is Avastin? What is the relationship between the NEJM article and “Ophthalmologygate” and why has this drug caused such a public outcry? Shanghai “Ophthalmologygate”: Avastin = fake drug? On September 10, 2010, the Shanghai Municipal Health Bureau issued a notice stating that a hundred patients in the ophthalmology department of Shanghai First People’s Hospital (hereinafter referred to as “Shanghai First Hospital”) had received intravitreal topical treatment for “age-related macular degeneration” a few days earlier, and had been injected with a drug called “Avastin”. “A total of 61 patients were admitted to the hospital as of that morning, and all of them were diagnosed as “endophthalmitis”. The focus of attention soon fell on Avastin and its injection process, which at first was thought to be a matter of intraoperative infection. However, it was a surprise that Roche Pharmaceuticals, the manufacturer of Avastin, said that Avastin’s indication was only in the field of oncology treatment and that it was approved but not officially marketed in China, let alone for ophthalmic patients. Sure enough, this batch of Avastin labeled as Roche production was subsequently identified by the relevant departments as a “fake drug”, and was sold to the Shanghai Rui’an Clinic after a number of people changed hands, and then by its flow into the city’s first hospital ophthalmology use. The name “fake drug” immediately caused an uproar. Many media and the public threw out the words “black heart”, “profit-oriented”, “smuggling” and so on, attacking the irregularities of the city hospital. However, many insiders in the ophthalmology industry are seeking justice for Avastin. They believe that, for the time being, without looking into whether these patients’ endophthalmitis originated from the drug itself or the infection caused during the dispensing process, Avastin is a drug that has good and safe effects on age-related macular degeneration and is relatively inexpensive, so ophthalmologists at home and abroad often use this drug “illegally. In short, Avastin for age-related macular degeneration has been an “open secret” for a long time. Avastin, also known as Bevacizumab, is an anti-tumor drug launched by the American biopharmaceutical giant Genentech (currently part of Roche) in 2004. Currently, the FDA-approved indications for Avastin are limited to oncology treatment. When ophthalmologists discovered the “open secret” that Avastin could treat eye disease, Genentech was inspired to develop a new drug, Lucentis, also known as Ranibizumab, specifically for eye disease, which was approved for marketing by the FDA in 2005. It was approved by the FDA in 2005. However, Lucentis has not been well received by the ophthalmology community. What is the reason for this? Which is better in terms of efficacy, Avastin or Luminol? If Avastin is comparable to Leminophthalmus in terms of efficacy, as confirmed by many clinical practices, then Huyi Hospital’s practice is justifiable; if Avastin is inferior to Leminophthalmus, then Huyi Hospital will be charged with the double crime of “over-indication + irrational use” and be condemned for both medical skill and medical ethics. NEJM authoritative ruling: Avastin = good medicine! On April 28, the CATT (Comparison of Age-Related MacularDegeneration Treatment Trials) study, a clinical trial of Avastin and Luminol for the treatment of age-related macular degeneration, was finally released. The results of the trial are a relief: in terms of 1-year results, the two were equally effective in treating the same usage. The CATT study, co-led by the National Eye Institute (NEI) and the National Institutes of Health (NIH), used a multicenter randomized, single-blind controlled approach. Inclusion criteria for subjects included being 50 years of age or older, having age-related macular degeneration (AMD, also known as age-related macular degeneration) resulting in the presence of untreated active choroidal neovascularization in one eye, and having visual acuity between 20/25 and 20/320 (as measured by an electronic visual acuity tester). The researchers then divided the more than 1,000 subjects into four groups: regular injections of Lemming Eye every 28 days (monthly Lemming Eye group); regular injections of Avastin every 28 days (monthly Avastin group); injections of Lemming Eye only when active neovascularization was present (as-needed Lemming Eye group); and as-needed Avastin group. For subjects in the latter two groups, ophthalmologic examinations, including time-domain optical correlation tomography (time-domain OCT), visual acuity, and fluorescein fundoscopy, were performed every 28 days to check for active neovascularization, and if so, the appropriate drug was injected. The dose of each injection was 0.50 mg for Lemming Eye and 1.25 mg for Avastin, both dissolved in 0.05 mL of injection solution. Visual acuity values after 1 year of trial treatment showed little difference between monthly and as-needed treatment with Luminol, and comparable efficacy between as-needed treatment with Luminol and monthly treatment with Avastin. Notably, although there was no significant difference in efficacy between monthly and as-needed treatment, the average number of injections received in the Avastin and Lemming Eye groups was only 7.7 and 6.8 in the as-needed treatment, almost half of the monthly treatment group. The difference in the number of injections and medications also made a huge difference in the cost of treatment: the most expensive group was the monthly treatment group, which spent a total of$200 for 1 year, and the least expensive was the on-demand group, which spent only$385 for Avastin. Thus, the best of both worlds – equal efficacy and significant financial relief – makes Avastin a worthy “good drug”. (See NEJM. 2011, Apr 28 online for additional data on trial comparisons.) “Fake drugs”: price leverage is the real driver. At this point, the investigation into the Shanghai “Ophthalmologygate” case has come to an end. Avastin, considered a “fake” drug, has been completely “turned around” in the top medical journal NEJM, and has become a “good drug” with good value. In fact, the efficacy of Avastin in treating age-related macular degeneration has long been the consensus of the ophthalmology community, and this CATT clinical trial is just a more authoritative scientific “name” for Avastin. However, in accordance with the provisions of the Drug Administration Law of the People’s Republic of China, even if the Avastin used by Shanghai First Hospital is indeed produced by Roche, but it has been used privately without approval, and the indications used exceed the general scope, then the Shanghai First People’s Hospital, which enjoys the reputation of “stars in the sky and eyes in the city”, can not escape The charge of using “fake drugs”. It is because this “fake drug” cap has not been removed, Avastin’s packaging and circulation are always in the “dark”, and this greatly increases the possibility of drug infection. The original packaging of Avastin was 100 mg/4 ml for oncology only, and Roche has never produced a separate dosage package for ophthalmology, so the drug had to be split separately from 100 mg. In the CATT study, each dose of Avastin was 1.25 mg, which shows how many times it was split. The risk of infection of the drug would be greatly increased if the process of dispensing this additional agent was not strictly performed aseptically. In addition, Avastin is a biological preparation with high storage requirements, it needs to be stored at 2~8℃, not to be frozen or shaken, and must be used immediately after unpacking, so if it is not well stored, it will easily lead to deterioration and inflammation. Therefore, the reason for the collective infection of patients in Shanghai Hospital is likely to be a problem in the distribution and storage and transportation. In fact, the real cause of the “eye drug door” whether fake drugs or infections, a little common sense people will therefore be associated with the manufacturer of Avastin – Roche. If Roche could expand the indications of Avastin to the ophthalmic field, the production of packaging suitable for ophthalmic treatment, if the regulatory authorities can approve the drug “openly” used, then “ophthalmology door” is very likely not to happen. But what is the reason for Roche’s push for a new drug, Luminol? Avastin and Lemming Eye are both anti-VEGF monoclonal antibodies that act at the same site, but differ in molecular weight, affinity for VEGF, intraocular clearance rate and price. One of the most dramatic differences is the price: in terms of price per dose, Avastin costs only US$50, while Lemming Eye costs US$2,000, a 40-fold difference. It goes without saying that anyone would be tempted by such huge commercial benefits. This is also the real reason for forcing the majority of “conscientious” ophthalmologists to “operate behind closed doors” and use Avastin illegally. Therefore, the price leverage is the real driver of this “ophthalmology door” incident. Roche knew very well that the widespread use of Avastin would definitely affect the sales of Luminol. However, whether for strategic marketing reasons or driven by profit, Roche has not conducted clinical trials on Avastin for age-related macular degeneration, let alone expanded the indication. As a result, the American Academy of Ophthalmologists and the National Institutes of Health, at the call of ophthalmologists, funded tens of millions of dollars to conduct this CATT study instead of the drug company, with the aim, among other things, of using the gold standard to prompt Roche to do justice to Avastin at an early date. From the Avastin story, we can see the seemingly calm but dark game between the drug company and the clinic: as clinicians, it is incumbent on them to look out for the health and financial problems of their patients, while sometimes “good value” drugs are unprofitable for the drug company, so they try to deny production, narrow the scope of indications, or make the drug more expensive. or bring more expensive drugs to market. Avastin was the “victim” of this game, and both the drug company and the doctor were strongly condemned by public opinion in the “Ophthalmologygate” case, while the patients who could have benefited from it lost their already weak light, so to speak. This is a “triple whammy”. It is hoped that the CATT study will help end this “battle of Avastin” and bring true “sunlight” to patients with age-related macular degeneration who are on the verge of losing their sight.