Cross-linking platform denied FDA approval—for now

Cross-linking platform denied FDA approval—for now

In late February, a joint panel of the Food and Drug Administration voted to recommend Avedro’s corneal cross-linking platform for regulatory approval. The combined riboflavin ophthalmic solutions and ultraviolet light irradiation for corneal collagen cross-linking platform may be approved for the treatment of progressive keratoconus and corneal ectasia following refractive surgery. Unfortunately for Avedro, in late March the FDA opted to send a complete response letter denying the approval (for now).

The FDA “identified a small number of areas of the application concerning the device which require additional information, none of which pertain to the clinical study safety or efficacy data presented in the New Drug Application,” Avedro said in a news release.

While the Photrexa/KXL System is already commercially available in Europe and Asia, Avedro has had a hard time convincing US regulators of the benefit. The panel voted 10 to 4 with one abstention to endorse the drug for progressive keratoconus, and 6 to 4 with 4 abstentions and 1 uncast vote for corneal ectasia. According to several people in attendance, panel members suggested highlighting data deficiencies in the product’s label.

Stephen Feman, MD, opposed approval, citing a lack of data with the current device. The UVA irradiation device Avedro intends to market is not the same as it used in the clinical studies submitted to the FDA, he noted, suggesting there may be subtle device differences that impact visual outcomes. Jayne Weiss, MD, suggested the labeling reflect that different machines were used in the clinical studies. Others requested statements indicating that the long-term effects beyond 12 months are unknown.

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However, Avedro’s application includes data from three prospective, randomized, parallel-group, open-label, sham-controlled, 12-month trials conducted in the US to determine the safety and effectiveness of riboflavin ophthalmic solutions used in conjunction with UVA irradiation for performing corneal cross-linking in eyes with keratoconus and corneal ectasia following refractive surgery. The KXL system received orphan status in 2011, providing Avedro with 7 years of market exclusivity once approved.

Members of the American Society of Cataract and Refractive Surgery, the Cornea Society, and leading anterior segment surgeons all strongly support the approval of a collagen cross-linking device in the U.S. During the hearing, David Glasser, MD, spoke on behalf of the Cornea Society, urging members to recommend the submission saying if left untreated both keratoconus and ectasia later may require much more advanced surgical options.

Numerous studies (not just those involving the Avedro device) suggest cross-linking can stabilize keratoconus. By flattening the cornea (with or without an associated reduction in astigmatism), uncorrected visual acuity is typically improved, obviating the need for potentially uncomfortable contact lens wear and/or corneal transplants. The Eye Bank Association of America has estimated more than 40% of the corneal transplants in the U.S.—or more than 6,800 transplants—could be avoided if an approved device for cross-linking were approved to treat keratoconus.