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I have patients with post-refractive ectasia who might benefit from corneal collagen cross-linking with riboflavin (CXL/C3-R). Will OMIC cover this treatment?

Updated 4/22/2019

Corneal collagen cross-linking (CXL/C3-R/CXR/CCL/KXL) with riboflavin has been used extensively in Europe for the past decade, and interest in using this technology is gaining in the United States amid increasing favorable evidence that corneal cross-linking may ameliorate the progression of keratoconus and post-refractive ectasia while maintaining a reasonable safety profile.

Previously, OMIC insureds had to participate in clinical trials under and in accordance with an American IRB-approved protocol, use a drug granted orphan status in accordance with criteria established by the FDA for such designation, or obtain a compassionate use exemption.

In April 2016, the first cross-linking system became FDA-approved in the US.  Avedro received approval for Photrexa® and Photrexa® Viscous for use with the KXL® System in corneal cross-linking for the treatment of progressive keratoconus. In July, the FDA approved the Avedro device and solutions for the treatment of corneal ectasia following refractive surgery. In response to these new developments, OMIC policyholders who are rated Surgery Class 3 may use this FDA-approved system without restriction, including for off-label uses. Here is a link to our sample consent form: http://www.omic.com/corneal-crosslinking-consent-form/.

According to sources at the FDA, physicians must obtain IND (Investigational New Drug) approval before performing corneal cross-linking using any device or riboflavin solution(s) other than the KXL® System with Photrexa® and Photrexa® Viscous. (The FDA’s non-significant risk clause does not apply to drugs, biologics, or combinations that include a drug or biologic. Because use of riboflavin with a light source is a drug/device combination, it is regulated under an IND.) To improve the defensibility of claims, OMIC policyholders who perform cross-linking utilizing any devices other than the Avedro KXL® System or riboflavin solutions other than Photrexa® and Photrexa® Viscous must do so under and in accordance with an American IRB-approved protocol and obtain an IND from the FDA for the riboflavin solution until such other device or riboflavin solution obtains FDA approval for corneal cross-linking.  We have been informed that a single IND may be used for multiple solutions and/or devices. IRB approval may be obtained before, during, or after the IND becomes effective.

Clinical questions remain and are the subject of ongoing clinical trials and research. One key question is about technique. Some ophthalmologists advocate removing the corneal epithelium prior to application of the riboflavin eye drops. Others keep the epithelium intact. Studies support both positions. Some data in the literature shows that epithelial removal is critical for adequate penetration of the currently approved riboflavin drops, which in turn is critical for creation of the collagen cross-linking after exposure to the UV light. There is some literature also suggesting that alternative forms of riboflavin may allow for effective epithelium-on treatment.  However, there is some concern that an intrastromal application of riboflavin followed by UVA irradiation could cause damage due to free radicals created close to the endothelium. Reliable endothelial studies using that application have not yet been performed.

Managing patient expectations is a critical component in reducing risk. Patients should understand that the aim of corneal cross-linking is to halt the progression of ectasia, not to eliminate existing ectasia. And while studies suggest that cross-linking may stabilize progressive keratoconus, multiple treatments may be necessary to achieve that effect. Additionally, improvements in vision, keratometry, and topography are significantly variable in both progressive and non-progressive cases of keratoconus. Due to the lack of predictability of results as well as the potential for regression over time, care must be taken in the consent process to ensure realistic expectations. Discuss the off-label status of the procedure with the patient if cross-linking using the Avedro system is performed for treatment for conditions other than the FDA-approved “progressive keratoconus” and post-refractive ectasia, such as for non-progressive keratoconus or infectious keratitis, or for treatment of patients younger than 14 years old.

If another device and/or riboflavin solution is utilized, be sure that an IND is in effect and that the system is employed as part of an American IRB-approved protocol. Notify the patients of the procedure’s non-approved status and advise them that an FDA-approved treatment is available. (Changes to the consent form for existing clinical trials may be required.) Document these discussions appropriately in the medical record and informed consent document.

Regardless what system is used, careful consent procedures must be followed and established protocols must be rigorously adhered to in order to provide proper protection to both the patient and the physician.

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