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Deborah Fisher, a 65-year-old retired BC Ferries worker, seen at her home in West Vancouver in August, received 13 injections in her left eye over 18 months. Eventually, the intraocular pressure in her left eye rose to dangerous levels.Rafal Gerszak/The Globe and Mail

Two dozen ophthalmologists are accusing the B.C. government of failing to properly investigate concerns that a provincewide eye injection program could be putting patients at risk of developing severe glaucoma, according to a letter obtained by The Globe and Mail.

The letter also said that B.C.'s unique program for delivering the eye drugs – a program that pays a small group of retina specialists as much as $250,000 each annually, on top of billings that are already the highest in the province – has long been “clouded in secrecy.”

Eight months have passed since the NDP government announced that it would ask external experts to probe a possible link between glaucoma and injectable drugs taken by thousands of patients to ward off age-related macular degeneration, once the most common cause of irreversible blindness.

But the government has yet to publicly release any findings, and the signatories to the letter say the investigation that the province announced last spring does not go far enough.

“A proper study is urgently required to determine what the risk is and what the problem is,” according to the letter, signed by 24 ophthalmologists and e-mailed to B.C.’s Premier, Health Minister and other officials on Dec. 11. “A thorough analysis of all injection patients must be completed by external, arm’s-length, independent experts with full access to unedited raw data and then published; to date this has not occurred.”

Concerns about the safety of injectable eye drugs have shed new light on a little-known program that the B.C. government hails as a success: the Provincial Retinal Diseases Treatment Program. Established in 2009, the program has saved the province hundreds of millions in drug costs, allowing B.C. to offer the prohibitively expensive injections for free to all patients. On the other side of that cost-saving equation, the province is making generous payouts to 29 retina specialists, many of whom already bill the province more than $2-million a year.

The question of whether B.C. patients are actually experiencing an abnormal spike in glaucoma – a disease that damages the optic nerve and can cause blindness if left unchecked – is still an open one, according to Health Minister Adrian Dix and the Provincial Health Services Authority (PHSA), the agency that oversees the injection program.

Mr. Dix called in experts from the BC Centre for Disease Control and the Public Health Agency of Canada last May after the British Columbia Society of Eye Physicians and Surgeons sent a letter to the province warning that thousands of patients were being exposed to an "increased risk of severe glaucoma and peripheral blindness,” possibly because of toxins from plastic syringes leeching into the eye medications.

By that time, the PHSA, which had first been alerted to the apparent problem by front-line doctors in late 2017, had already conducted a three-phase review of internal injection data and a supply chain audit of how the medications were stored and handled.

The initial review found “found no conclusive evidence,” of a link between the injections and glaucoma surgery, and no concrete proof of syringe-related contamination, Mr. Dix said in an interview in the fall.

“But we’re not stopping there," he said. "We’re digging deeper into this issue than I think anyone has done and that takes some time.”

Ben Hadaway, a spokesman for PHSA, said by e-mail that the fourth phase of the investigation, the one involving outside epidemiological expertise, is expected to be completed in February. It will be made public, he said.

The B.C. Provincial Retinal Diseases Treatment Program covers a class of sight-saving medications known as anti-vascular endothelial growth factor, or anti-VEGF, drugs.

Injected into the eye as often as once a month, anti-VEGF drugs have revolutionized the treatment of age-related macular degeneration and other retinal diseases, including diabetic macular edema and retinal vein occlusion.

But anti-VEGF drugs come with a high sticker price.

Ranibizumab, sold under the brand name Lucentis, has a list price (the price before any confidential discounts are factored in) of $1,575 a dose. That works out to as much as $39,360 for two years of treatment, according to a 2016 report from the Canadian Agency for Drugs and Technologies in Health (CADTH), an agency that advises the provinces on which drugs to cover.

Another approved anti-VEGF drug, aflibercept, or Eylea, costs as much as $20,000 for two years of injections.

Mindful of the high prices of anti-VEGF drugs, Gordon Campbell’s Liberal government and an association of retina specialists in 2009 created the retinal diseases treatment program to facilitate the prescribing of a cheaper option: bevacizumab, or Avastin, a cancer drug that is similar to Lucentis but that is not approved by Health Canada or any other regulator to treat retinal diseases.

The reason? Avastin’s maker, Genentech, a subsidiary of Roche, has not applied for regulatory approval of Avastin as an eye drug, despite rigorous, publicly funded clinical trials showing Avastin is as safe and effective as its pricier cousin.

Genentech makes both Lucentis and Avastin. If the company licensed Avastin for retinal diseases, it would undercut the profit of its more expensive drug. Two years of Avastin injections cost $3,397, about one-10th the price of Lucentis, according to CADTH. (Genentech has consistently said that Avastin and Lucentis are different medicines, and that Lucentis is most appropriate for treating retinal diseases.)

The lack of formal licensing means that Avastin, which is sold in large vials geared toward oncology patients, has to be split, or compounded at a pharmacy into smaller doses for eye injections. That creates a risk for contamination. In B.C., however, all anti-VEGF drugs, not just Avastin, are compounded and put into syringes.

Under the B.C. government’s agreement with retina specialists, the ophthalmologists promise to prescribe cheaper Avastin 85 per cent of the time.

They also agree to participate in quality assurance and research activities, such as crafting clinical practice guidelines and reporting on the safety and effectiveness of every injection through a provincial database, which is now being mined for clues to the alleged glaucoma problem.

In exchange, the Provincial Health Services Authority pays the retina specialists a “program management fee,” for every injection, up to a maximum of $250,000 a year. Prior to 2013, the cap was even higher, at $360,000 a year, the PHSA said.

The program management fees are above and beyond what retina specialists already bill the province’s Medical Services Plan for performing anti-VEGF injections, and they’re not included in Blue Book figures that show nine of the province’s top 10 billers in 2018-19 were retina specialists. (Billings are not salaries; they don’t reflect overhead costs for staff and equipment, which are often high for ophthalmologists.)

The top billing doctor in B.C. last year was David Albiani, division head of the University of British Columbia’s Department of Ophthalmology and Visual Sciences. He billed $3,352,188.57, according to the Blue Book.

His practice, West Coast Retina, also received $791,000 in program management fees. That money would presumably be split with the other retina specialists at his clinic. Dr. Albiani did not return calls and e-mails seeking comment.

Dhar Dhanda, a retina specialist who was the highest biller in the province for five of the past seven years, billed $3,246,586.06 in 2018-2019, third overall.

PHSA also paid $247,675 in program management fees to MGKD Medical Ltd., a company registered to Harvinder Kaur Phandal-Dhanda, someone with the same name as Dr. Dhanda’s wife. Dr. Dhanda did not respond to calls, e-mails and a letter sent by courier to his office.

Derek Godinho, president of the Association of British Columbia Retina Specialists, defended the financial arrangement, pointing out that in 2018-19, more than 21,300 patients received sight-saving anti-VEGF injections at no cost, while the government spent millions less on Avastin than it would have on Lucentis or Eylea.

“The retina specialists in this program have, for 10-plus years, provided the highest level of care and the best access in the most cost-effective scenario in any jurisdiction," Dr. Godinho said. “[They’ve] also participated in all the other aspects of quality control, safety monitoring and data management."

Dr. Godinho, the 10th-highest biller in the province in 2018-19, billed $2,697,087.71 and received an additional $247,800 in program management fees last year.

The Provincial Retinal Diseases Treatment Program remained largely under the radar until glaucoma specialists and a handful of retina specialists began noticing that some anti-VEGF recipients in the province were experiencing abnormally high intraocular pressure, leading them to be rushed into emergency glaucoma surgery.

Andrew Merkur, a Vancouver retina specialist, painted a disturbing picture of the situation during a presentation at the University of British Columbia in March of 2019, a recording of which was viewed by The Globe and Mail.

“We audited our own practice," Dr. Merkur told the audience, “and we found that compared to what’s going on in the rest of the world, the U.S. and the rest of Canada, our relative risk of an [anti-VEGF] patient going on to glaucoma surgery is a relative risk of 125 per cent. So it’s not small. This is a disturbing number. An outbreak number, I would say." (Relative risk measures the likelihood of an event happening in one group versus another.)

Dr. Merkur told the crowd he flagged the issue for the PHSA, the Canadian Retinal Society and the company that makes the plastic syringes used to administer all three brands of anti-VEGF drugs in B.C. – anyone who might help get to the bottom of things.

Dr. Merkur declined an interview request.

Barend Zack, a Surrey glaucoma surgeon who organized the December letter co-signed by 23 of his colleagues, described the cases of what he calls anti-VEGF glaucoma as very severe, resistant to treatment with prescription eye drops and "quite different from the average glaucoma patient that I operate on.”

Take the case of one of Dr. Zack’s patients, Deborah Fisher, a 65-year-old retired BC Ferries worker who received 13 injections of Avastin in her left eye over 18 months, beginning in June of 2017.

Right before her first injection, the pressure readings in Ms. Fisher’s left and right eyes were 20 and 13, respectively – high, but not alarmingly so.

Normal eye pressure readings are in the range of 10 to 20. Higher pressures, if left unchecked, can damage the optic nerve that transmits visual information from the retina to the brain, causing irreversible blindness.

Over time, the intraocular pressure in Ms. Fisher’s left eye rose to dangerous levels. Prescription eye drops failed to control it.

On Oct. 3, 2018, Ms. Fisher underwent an emergency gonioscopy-assisted transluminal trabeculotomy, a minimally invasive surgery to relieve the pressure in her left eye.

By February of 2019, after receiving more Avastin injections, Ms. Fisher’s left-eye pressure peaked at a frightening 47. “It felt like there was a hot iron right in the middle of my eye,” Ms. Fisher said. “It just kept watering and I couldn’t see out of it. Everything was white.”

It’s difficult to say whether the anti-VEGF injections actually caused Ms. Fisher’s intraocular pressure to spike.

In fact, Ms. Fisher’s case would have been excluded from PHSA’s earlier review of the data because she was receiving Avastin for retinal vein occlusion and macular edema, two conditions that, on their own, increase the risk of glaucoma.

The PHSA also excluded anti-VEGF recipients who had a history of taking glaucoma medications or who had undergone a previous glaucoma surgery – the goal being to filter out patients who might have required glaucoma surgery anyway, even if they had never received a single anti-VEGF injection.

The upshot: Of 18,946 B.C. patients who received a first injection of Avastin, Lucentis or Eylea between Jan. 1, 2011, and Dec. 31, 2015, 11,113 patients – nearly 60 per cent of the total – were excluded from the PHSA’s analysis.

Of the 7,833 who remained, only 0.5 per cent over all went on to receive glaucoma surgery within two years. The surgery rates were higher among patients who received more injections: 1.5 per cent for those who received between nine and 13 injections annually and 2.7 per cent for those receiving more than 13 injections a year.

Mr. Dix and PHSA officials said those findings did not warrant cancelling the Provincial Retinal Diseases Treatment Program outright, especially considering how crucial anti-VEGF injections are to preserving the sight of thousands of British Columbians.

That’s not good enough for Dr. Zack, the Surrey glaucoma surgeon who spearheaded the December letter.

He and the other signatories say that, at least “until the magnitude and scope of the problem have been accurately assessed,” patients should receive only the more expensive Health Canada-approved anti-VEGF injections that come in single-use vials, directly from the manufacturer.

“The simple reason is patient safety,” Dr. Zack said, “And while there’s a controversy here, we feel strongly that patients should be protected.”

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