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FDA panel recommends approval of riboflavin/UVA cross-linking system
Panel members raise concerns about study methodology and the use of an older version of the system’s ultraviolet light source.
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Amid concerns about study data and methodology, a joint panel of the FDA’s Dermatologic and Ophthalmic Drugs Advisory Committee and Ophthalmic Devices Panel recommended approval of Avedro’s combined riboflavin ophthalmic solutions and ultraviolet light irradiation for corneal collagen cross-linking. The panel voted on Feb. 24.
Photrexa Viscous (riboflavin ophthalmic solution with 20% dextran)/Photrexa (riboflavin ophthalmic solution with 0% dextran) with the KXL system (UVA light) is the first cross-linking treatment to be considered for approval in the U.S.
The riboflavin solutions and UV irradiation device are indicated for progressive keratoconus and corneal ectasia following refractive surgery.
The panel voted on the cross-linking system for both indications.
Panel votes and comments
On the question, “Has substantial evidence of efficacy and safety been demonstrated for the drug-device combination of Photrexa Viscous and Photrexa riboflavin ophthalmic solution and the KXL system (UVA light) to support approval for progressive keratoconus?,” 10 panel members voted yes, four voted no and one abstained.
Michael W. Belin
Temporary member Michael W. Belin, MD, explained his “no” vote.
“I would actually hope that the FDA would approve cross-linking based on the available data and to approve riboflavin and UV for any manufacturer that uses good manufacturing practices,” Belin said. “But just based on this study, I think it was a poorly done study, and I don’t understand why, when they took over the data 5 years ago and realized it was poor, they didn’t do an additional arm to validate the data.”
On the question, “Has substantial evidence of efficacy and safety been demonstrated for the drug-device combination of Photrexa Viscous and Photrexa riboflavin ophthalmic solution and the KXL system (UVA light) to support approval for corneal ectasia following refractive surgery?,” six panel members voted yes, four voted no and four abstained. One member, Belin, did not vote.
Member Stephen S. Feman, MD, MPH, FACS, attributed his “no” vote to Avedro’s lack of data on the KXL device; the company’s IROC UV-X Illumination System was used in the clinical trial.
“No one has done the study using the device that’s been planned to be used, and we have no data as to whether or not the device works appropriately with this medication,” Feman said.
Panel members also voiced concerns about endothelial cell density and study methodology, particularly a change in data analysis that moved the primary efficacy endpoint from 3 months to 12 months.
Clinical trial results
Avedro’s new drug application is based on three phase 3 prospective, randomized, controlled clinical trials. In each study, patients were randomized 1:1 to undergo cross-linking or sham treatment. The primary efficacy endpoint was corneal curvature as measured by maximum keratometry.
The company’s decision to change the primary efficacy endpoint from 3 months to 12 months was based on findings that 3 months is insufficient time to analyze the benefits of cross-linking, according to Avedro’s briefing document.
Safety endpoints included adverse events, visual acuity and endothelial cell density.
Results showed that patients with progressive keratoconus and corneal ectasia had a significant change in corneal curvature (P < .0001).
The most common adverse events were corneal haze, punctate keratitis, corneal striae, corneal epithelial defect, eye pain, reduced visual acuity and blurred vision. Adverse events were generally mild, and their incidence was low (1.1% or less).
A 3-year phase 4 study with about 500 eyes is planned, according to David Muller, PhD, president and CEO of Avedro.
Testimony
During an open public hearing, Paula Cofer, an advocate for patients with corneal ectasia following refractive surgery, said permanent weakening of the cornea led to a 2011 petition to the FDA to withdraw approval of LASIK devices.
“Most cases of ectasia are never reported to the FDA, and the true rate is unknown,” Cofer said. “LASIK surgeons advising the FDA were more interested in maximizing the pool of candidates than in patients’ best interests.”
Other speakers questioned the reported incidence of corneal ectasia, said LASIK should not be performed and cited reports of depression stemming from LASIK-related adverse events.
David B. Glasser, MD, representing the Cornea Society, said cross-linking will reduce the need for corneal transplantation or other invasive surgery, and will extend and improve contact lens tolerance.
Stephen G. Slade, MD, OSN Refractive Surgery Board Member, called cross-linking a “patient-friendly technique” that halts the progression of keratoconus in a majority of cases.
“This is the pure science. This is fighting blindness,” Slade said. “Nothing could make me happier than to have a technique such as cross-linking where I can say that I have done my last graft on a keratoconus patient.”
Thomas John, MD, OSN Cornea/External Disease Board Member, said the American Society of Cataract and Refractive Surgery supports the approval of corneal collagen cross-linking. – by Matt Hasson
References:
Corneal collagen cross-linking with Photrexa Viscous (riboflavin ophthalmic solution) 20% dextran, Photrexa (riboflavin ophthalmic solution)/KXL system: NDA 203324. www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/DermatologicandOphthalmicDrugsAdvisoryCommittee/UCM436471.pdf. Feb. 24, 2015.NDA 203324: Photrexa Viscous and Photrexa (riboflavin ophthalmic solution)/KXL system (UVA light source). www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/DermatologicandOphthalmicDrugsAdvisoryCommittee/UCM436470.pdf.
Perspective
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A. John Kanellopoulos, MD
In my opinion, this is a logical step considering all the evidence-based science showing cross-linking’s efficacy in halting corneal ectasia. Its potential FDA approval will allow thousands of patients in the U.S. to be treated legally to avoid ectasia progression and cornea transplantation.
Through the last 2 decades, corneal collagen cross-linking has grown internationally from an experimental procedure used as a last resort prior to cornea transplantation to a whole anterior segment subspecialty.
Cross-linking has established safety and efficacy in numerous European studies initially and, after that, in other continents. It has emerged as a significant option in young keratoconus patients as a prophylactic measure for potential ectasia progression.
Our clinical team in Athens has contributed several new techniques and technology advancements over the last 12 years that are currently used clinically in most of the world, such as higher fluency cross-linking, combining cross-linking with a topography-guided excimer laser normalization of the ectatic, irregular cornea surface, using cross-linking in situ through a femtosecond laser pocket, and combining high fluency cross-linking and routine hyperopia and higher myopia LASIK. The last 2 years, we have additionally introduced using variable fluency, topography-designed cross-linking patterns in order to predictably correct refractive errors such as low myopia, hyperopia and/or astigmatism. My personal opinion as a clinician is that FDA approval in the U.S. is long overdue.
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