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Issue: December 25, 2018
December 19, 2018
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Improved communication evident in FDA approval process for 2018

Issue: December 25, 2018

More meaningful endpoints for clinical trials, better communication for necessary study designs and an improved approval process have led to more efficient FDA approvals for ophthalmologic drugs and devices in 2018.

While there have been few drastic changes in the FDA’s approval process in the last 30 years, communication between the FDA and medical industry has improved, Wiley Chambers, MD, deputy director of the Division of Transplant and Ophthalmology Products at the FDA, said.

“There has been a strong belief, during the entire time I’ve been here, that there should be as much open communication as possible. One of the worst things that can happen during drug development is for a drug company to do a trial, a study, an investigation and generate information because they think the agency wants it when we don’t think it’s important. The company doesn’t think it’s important — they’re just doing it because they think we think it’s important and they never ask. So, if we can eliminate people doing unnecessary work, we think that’s helpful for everyone,” Chambers said.

John A. Hovanesian, MD, FACS
The FDA’s emphasis on open communication has led to greater success for both drug and device approvals, according to John A. Hovanesian, MD, FACS.

Source: John A. Hovanesian, MD, FACS

Communication improving

The FDA encourages communication at all points during the approval process. If a company has a question about the process or what should be included in a clinical trial, it is encouraged to communicate with the FDA for straightforward answers, Chambers said.

With this improved communication, practitioners are seeing new technologies being approved by the FDA and more success with all approvals in general, OSN Cataract Surgery Section Editor John A. Hovanesian, MD, FACS, said.

“It’s refreshing that the FDA is back to approving both drugs and devices because we’ve suffered a time of stagnation where very good products had a hard time getting through to approval. The agency has clearly streamlined its process, and it has become more technology friendly. This means a few things for practitioners. We’ll start to see these new technologies become available, and we can anticipate more on the horizon. As angel investors and venture capital firms see approvals happening and companies succeeding, they’re going to invest in new technology, which is great for our patients and great for us,” he said.

Cataract surgery-related approvals

As of press time, the FDA issued seven cataract surgery-related approvals in 2018, including drugs for treatment of pain and/or inflammation associated with cataract surgery and stents for reduction of IOP in adult patients with mild to moderate primary open-angle glaucoma undergoing cataract surgery.

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On Dec. 3, Ocular Therapeutix received FDA approval for Dextenza (dexamethasone ophthalmic insert 0.4 mg) intracanalicular insert to treat postoperative ocular pain for up to 30 days with one treatment.

Kala Pharmaceuticals received FDA approval for Inveltys (loteprednol etabonate ophthalmic suspension 1%), a twice-daily steroid, for the treatment of postoperative inflammation and pain after ocular surgery. Icon Bioscience — now EyePoint Pharmaceuticals — received approval for Dexycu (dexamethasone intraocular suspension 9%), a single-dose, sustained-release steroid injection for the treatment of inflammation associated with cataract surgery.

These approvals should mean less frequent administration of drops or no administration of topical steroid drops after cataract surgery, Hovanesian said.

“One of the most common complaints we don’t think about as clinicians is the inconvenience of taking drops. Our patients delay travel because they worry about inability to get their drops while traveling; they plan family events after their drops are going to be finished because it’s a confusing and difficult process. If we can eliminate that, think of the convenience that would lend patients. It would also increase the compliance for so many of them,” he said.

Glaukos and Ivantis both received approval for minimally invasive glaucoma surgery (MIGS) devices for the reduction of IOP in adult patients with mild to moderate primary open-angle glaucoma who are undergoing cataract surgery.

The iStent inject trabecular micro-bypass system (Glaukos) is designed to optimize the natural outflow of aqueous humor, creating two patent bypasses through the trabecular meshwork for multidirectional flow through Schlemm’s canal.

The Hydrus microstent (Ivantis) is designed to reduce eye pressure by re-establishing flow through Schlemm’s canal. The microstent creates a bypass through the trabecular meshwork, and dilates and scaffolds the canal to augment outflow, according to the company website.

“This year we have the approval of the iStent inject and the Ivantis Hydrus implant, both devices I’ve had a chance to implant and like very much. ... By approving more MIGS devices, we legitimize MIGS as a field that’s here to stay. With the new devices, especially the iStent inject, we have an easier implantation technique for surgeons. Every cataract surgeon needs to start performing MIGS because it’s doable and it’s good for the patient,” Hovanesian said.

Clinical trials that led to FDA approval demonstrated that the Hydrus microstent has “very aggressive” pressure-lowering capability. Its large size can be intimidating for a surgeon to implant, but the implantation is “quite intuitive” and has a short learning curve for surgeons, Hovanesian said.

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This past year, the FDA also granted approval to HumanOptics for the CustomFlex artificial iris, which is indicated to treat congenital aniridia, as well as iris defects. Additionally, Omeros announced approval of a new indication for Omidria (phenylephrine 1% and ketorolac 0.3% intraocular solution) for pediatric patients.

Glaucoma surgery approvals

This has been a dynamic and rapidly changing period in the surgical glaucoma space with the approvals of the iStent inject and the Hydrus, OSN Glaucoma Surgery Section Editor Thomas W. Samuelson, MD, said.

Both devices have unique attributes and are welcome additions to the MIGS portfolio of procedures. It is difficult for the occasional glaucoma surgeon to master all the MIGS procedures, but it is useful to become familiar with more than one approach, he said.

Thomas W. Samuelson, MD
Thomas W. Samuelson

“The obvious advantage of iStent inject is that two devices are implanted in a single setting, increasing the chance that a major collector channel may be tapped into. Likewise, the 8-mm expanse of the Hydrus microstent increases the probability that more collectors will be within the region influenced by the device. Many surgeons will like the elegant ‘straight-on’ approach inherent to the iStent inject system and will find it less intimidating than devices passed circumferentially within the canal. Likewise, most surgeons familiar with the Hydrus describe a fairly short and favorable learning curve. In the HORIZON trial, the U.S. PMA study for Hydrus, 97% of patients randomized to the Hydrus group were successfully implanted, with 86% implanted on the initial attempt,” Samuelson said.

The devices have different qualities that may appeal to individual surgeons and patients. The Hydrus has a trimodal mechanism of action and as favorable 2-year data as any published in the MIGS space. The iStent inject is minimally disruptive, leaving the normal canal ultrastructure intact, which is potentially important in mild to moderate glaucoma patients, he said.

“Time will tell which approach will appeal to the majority of surgeons. Suffice it to say that both devices join an expanding portfolio of canal-based options, which now includes three device options, as well as inner wall ablative and canal-dilating procedures,” Samuelson said.

CyPass removal

On Aug. 29, Alcon removed its MIGS device, CyPass, from the market due to concerns about endothelial cell loss. The FDA approved CyPass based on 2-year safety and efficacy data while also mandating a post-approval study to collect 5-year safety data.

Based on the 5-year data, a subclinical finding was identified before patients had clinical signs or symptoms, and Alcon acted “swiftly, decisively and transparently” to voluntarily withdraw CyPass from the global market, Samuelson said.

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“In my opinion, CyPass is safer than many of our existing options used for more refractory glaucoma. Recall, the safety comparator in the COMPASS XT trial was phacoemulsification alone. It isn’t surprising that phacoemulsification combined with CyPass has more endothelial risk than the phaco-alone control group at 5 years. The fact is, existing long tubes such as Ahmed and Baerveldt likely have greater endothelial risk than CyPass. However, such comparison is speculative as no such 5-year data exist for our traditional surgeries. This underscores that the quality of data that we are obtaining for the MIGS [randomized controlled trials] is unprecedented in our field,” he said. “Of course, long tubes are used in higher risk disease, likely the better target population for CyPass as well.”

New glaucoma drugs

The past year also saw the approval of BAK-free glaucoma management drug Xelpros (latanoprost ophthalmic emulsion 0.005%, Sun Pharmaceutical) for the reduction of elevated IOP in open-angle glaucoma or ocular hypertension.

Elizabeth Yeu, MD
Elizabeth Yeu

“While the surgical management of glaucoma has commanded most of the headlines in recent years as MIGS procedures have become more widely adopted, 2017-2018 might be remembered as the year that ‘pharma fought back,’” Samuelson said, citing also the late 2017 FDA approvals of Vyzulta (latanoprostene bunod ophthalmic solution 0.024%, Bausch + Lomb) and Rhopressa (netarsudil ophthalmic solution 0.02%, Aerie Pharmaceuticals). “Of these, netarsudil is certainly the most novel, representing the first new drug class for the management of glaucoma in nearly 20 years. Latanoprostene bunod can arguably stake a claim as the single most potent eye drop available, and of course, BAK-free agents are very welcomed in this era of greater awareness of the ocular surface,” Samuelson said.

The drugs and surgical procedures approved for the glaucoma landscape in 2018 have enhanced a surgeon’s ability to move away from high-risk surgical procedures and complex multidrug regimens. The “MIGS plus meds” option to treat glaucoma, utilizing the best of surgical glaucoma enhanced by the best pharmacologic options, is becoming an approach favored by surgeons and patients alike, he said.

Cornea-related approvals

The FDA has been receptive and helpful in its guidance as it relates to how to approach clinical trials with regard to their study design, OSN Cornea/External Disease Section Editor Elizabeth Yeu, MD, said.

Yeu noted the importance of approvals for different drug delivery systems after cataract surgery to help obviate the need for topical steroids in 2019 and years forward.

“An intracameral dexamethasone or an intracanalicular dexamethasone plug, something that takes the need of compliance or topical toxicity out of the picture, is very important,” she said. “Anything we can do there is obviously going to help our patients who are vulnerable after ocular surgery or are older — both high-risk groups for dry eye disease or ocular surface disease. Whatever we do with respect to surgery will affect the cornea in the healing process.”

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Whereas Yeu looks forward to the possibility of FDA approvals in 2019 for new formulations of topical steroids to help heal post-surgical or inflammatory ocular conditions, 2018 did see some “exciting” approvals. Cequa (cyclosporine ophthalmic solution 0.09%, Sun Pharma), the highest FDA-approved concentration of cyclosporine A, was approved for the treatment of dry eye disease. The drug is designed to increase tear production in patients with keratoconjunctivitis sicca.

Area of need

Neurotrophic keratitis, an area of true need that currently has a lack of therapeutics, saw a turnaround this year with the approval of Oxervate (cenegermin, Dompé farmaceutici SpA) in late August, Yeu said.

Oxervate is the first FDA-approved drug to treat neurotrophic keratitis, a rare disease that affects the cornea. The topical eye drop demonstrated complete corneal healing in 8 weeks for 70% of patients treated.

Two companies that received acknowledgment for bimatoprost ophthalmic solution 0.03% for treatment of hypotrichosis of the eyelashes are Akorn, which received FDA approval of its abbreviated new drug application (ANDA), and Alembic Pharmaceuticals, which received tentative approval of its ANDA.

The FDA also approved oral 8 mg moxidectin, developed by Medicines Development for Global Health and the World Health Organization Special Programme for Research and Training in Tropical Diseases, for the treatment of onchocerciasis in patients 12 years and older.

Retina-related approvals

Improved drug delivery and drug packaging improvements highlighted the FDA approvals in 2018 for retina and vitreous surgery, OSN Retina/Vitreous Section Editor Andrew A. Moshfeghi, MD, MBA, said.

Andrew A. Moshfeghi, MD, MBA
Andrew A. Moshfeghi

Genentech received approval for Lucentis (ranibizumab) 0.3 mg prefilled syringes for all forms of diabetic retinopathy, an effective new item to improve patient safety by minimizing the additional handling of the drug, the syringe and the vial, and by eliminating additional steps that could lead to contamination, Moshfeghi said.

“I’m a huge fan of the prefilled syringe. It’s a nice, elegant design and extremely helpful in improving the efficiency of my clinic flow for patients receiving ranibizumab 0.3 mg compared with the previous iteration of the drug, which was a hassle. I look forward to seeing those patients who are treated with the prefilled syringe because I know it will be a nice, smooth experience,” he said.

Recently, the FDA has begun to allow for shorter primary endpoints of its clinical trials, making the approval process more streamlined. For example, in previous wet age-related macular degeneration clinical studies, the primary endpoint was typically at 1 year in a 2-year study, with at least another year of follow-up, Moshfeghi said.

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Diabetic macular edema clinical trials typically included a 2-year primary endpoint in a 3-year study, with an additional year of follow-up, he said.

Now, for some retinal studies with 1-year follow-up, the end point is even earlier. “I think that’s a step in the right direction, and it basically indicates that there is a prevailing, common understanding that some of the early anatomic and visual benefits that are achieved with the pharmacotherapeutic agents available now, if they’re recognized early in a robust manner, will continue as long as the treatments continue. We’ve had many years of many different clinical trials which serve as an underpinning for that relaxation of the guidelines,” Moshfeghi said.

The FDA also approved a supplemental biologics license application for a 12-week dosing schedule of Eylea (aflibercept, Regeneron) in patients with wet AMD. Eylea had previously been approved for dosing intervals of every 4 weeks or every 8 weeks, after three initial monthly doses.

Refractive surgery-related approvals

John P. Berdahl, MD
John P. Berdahl

The FDA has made a concerted effort to approve high-quality products in which the risk-benefit ratio is in favor of the patient. Both the FDA and industry have addressed legitimate concerns about the approval process, OSN Refractive Surgery Section Editor John P. Berdahl, MD, said.

Berdahl said 2018 not only brought several incremental improvement approvals for existing technologies, but also a major FDA premarket approval for ReLEx SMILE (Carl Zeiss Meditec) to treat myopic patients with astigmatism.

“The blessing is we have really good solutions, and I’m very proud of companies that continue to innovate and try to take that really high bar and push it higher. SMILE is a really good example of that. They’re doing the real hard work to improve upon an already great procedure like LASIK in a different way. With their myopia approval, and now their myopia and astigmatism approval, I think that they’re a welcome addition to the refractive surgery landscape,” he said.

Meaningful progress was also made this year with the approval of the Visian toric ICL (STAAR Surgical) for the correction of myopia with astigmatism and the enVista toric MX60T hydrophobic acrylic IOL (Bausch + Lomb) for astigmatism correction, he said.

The 2018 FDA approval of the iDESIGN Refractive Studio for LASIK (Johnson & Johnson Vision) saw an already existing technology improved, Berdahl said.

“Then you have approvals that are refractive in intent even though they’re around things like cataract surgery. Zepto (Mynosys), for example, in an attempt to get more predictable refractive outcomes with cataract surgery, things like Zepto are trying to add to precision in cataract surgery, and then the same thing in lenses. We’re making meaningful progress year after year, and most of the progress is going to be incremental in nature, but occasionally things like SMILE are going to be an entirely new approach to the procedure,” he said.

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This past year has seen the approval of a variety of products, indications and modifications of technology that are safe and efficacious for clinicians. However, how they perform on the market remains to be seen, Chambers said.

“From our perspective, it’s to give clinicians choices. We can continue to encourage new products. We think there is room for additional benefits through pharmacological agents for both patients and surgeons and additional tools for clinicians. We look forward to people continuing to develop products so that we can approve safe and efficacious new products,” he said. – by Robert Linnehan

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  • For more information:
  • John P. Berdahl, MD, can be reached at Vance Thompson Vision, 3101 W. 57th St., Sioux Falls SD 57108; email: john.berdahl@vancethompsonvision.com.
  • Wiley Chambers, MD, can be reached at Food and Drug Administration, Center for Drug Evaluation and Research, Office of Antimicrobial Products, 10903 New Hampshire Ave., Silver Spring, MD 20993; email: alison.hunt@fda.hhs.gov.
  • John A. Hovanesian, MD, FACS, can be reached at Harvard Eye Associates, 24401 Calle De La Louisa, Laguna Hills, CA 92653; email: drhovanesian@harvardeye.com.
  • Andrew A. Moshfeghi, MD, MBA, can be reached at USC Roski Eye Institute, Keck School of Medicine, University of Southern California, 1450 San Pablo St., 4th Floor, Los Angeles, CA 90033; email: amoshfeghi@gmail.com.
  • Thomas W. Samuelson, MD, can be reached at Minnesota Eye Consultants, 710 E. 24th St., Suite 100, Minneapolis, MN 55404; email: twsamuelson@mneye.com.
  • Elizabeth Yeu, MD, can be reached at Virginia Eye Consultants, 241 Corporate Blvd., Suite 210, Norfolk, VA 23502; email: eyeu@vec2020.com.

Disclosures: Berdahl reports he is a consultant for RxSight, Johnson & Johnson, Alcon, Carl Zeiss Meditec and Bausch + Lomb. Chambers reports no relevant financial disclosures. Hovanesian reports he is a consultant for Glaukos, Ivantis, Kala Pharmaceuticals, EyePoint, Ocular Therapeutix and Bausch + Lomb. Moshfeghi reports he is a consultant for and receives research funding from Regeneron and Genentech. Samuelson reports he is a consultant for Glaukos, Ivantis and Alcon Surgical. Yeu reports she is a consultant of Ocular Therapeutix, Alcon, Kala Pharmaceuticals, Shire and Sun Pharmaceutical Industries.

Click here to read the POINTCOUNTER, “What possible FDA approval in 2019 do you believe will have the most impact on ophthalmology?”