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EW SHOW DAILY 26 Corneal collagen crosslinking and its future in the U.S. M ichael W. Belin, MD, chair of the ASCRS FDA Committee, mod- erated a symposium to discuss crosslinking outside the U.S. and its potential future approval inside the U.S. "It's considered the standard of care out- side the U.S.," he told attendees, but there is no estimated timeline for approval in the U.S. Wiley Chambers, MD, deputy director of the Division of Trans- plant and Ophthalmology Products in the Center for Drug Evaluation and Research at the FDA, empha- sized the FDA's need for good data in order to approve a new drug. He said the primary basis for approval of any drug in the U.S. is that its benefits must outweigh the risk "when the drug product is taken by the in- tended population as labeled." The FDA has seven requirements for the data they evaluate, and Dr. Chambers noted that the FDA does not necessarily discount a trial con- ducted outside the United States. "You can use previously conducted trials if they were adequate and well- controlled," he said. "They need to use the same drug and the same de- vice in the same way it would be in the U.S." The issue with crosslink- ing, he said, is that data hasn't been submitted that meets that criteria. Crosslinking studies Sheraz M. Daya, MD, said of the more than 600 publications in PubMed on collagen crosslinking, the majority evaluated the proce- dure in the treatment of kerato- conus. There are three different procedures—epithelial-on, epithe- lial-off, and epithelial disruption. The evidence on its use for bullous keratopathy seems uneven, he said, with most groups reporting initial improvement but regression to preop levels within a fairly short timeline. There's not enough data out there yet to determine whether crosslinking should be used for this indication, he said. Fewer papers are published on microbial keratitis, and crosslinking "seems to be more ef- fective in bacterial infections than in fungal infections," Prof. Daya said. "Riboflavin has been demon- strated to be safe," he said. "From my point of view, epi-off crosslink- ing arrests the progression of kerato- conus, provides improved visual acuity and is safe. When you con- trast that with the inevitable PK pro- cedure, it's really a better option." Speaking about the complica- tions of crosslinking, Simon J. Dean, FRANZCO, New Zealand, said there are potential complica- tions including corneal haze. "The complication rate is around 5–10%, with most of the higher reported rates corresponding to higher haze. The infection rate is around 2% with epi-off and bandage contact lenses. Yet none of the patients suffered vi- sual loss," he said. In isolated cases, endothelial failure led to corneal graft, and one case of corneal perfo- ration has been reported. Can sur- geons promise an improvement after crosslinking in keratoconus and ec- tasia? Maybe, he said, but surgeons can promise the procedure will halt progression. Further, the risk of a complication remains fairly low. In New Zealand, where regulatory approval is not as stringent and crosslinking took 3 months from submission to approval, crosslinking is being used prophylactically in "healthy" ametropic laser refractive surgery patients (iatrogenic corneal weakening). Analyzing the costs In the 1970s, products took 1 to 3 years before they were approved, but now it's closer to 5 to 10 years, said William Link, PhD, Versant Ven- tures, San Francisco. Reimbursement used to be third party only, and now it is combination, he said. Most importantly, "the cost to bring something to market used to be $5 to $10 million, and now it's upward of $200 million," he said. The risk profile strongly impacts every stage of the process. "There are considerably fewer dollars being invested in the U.S. to bring products to market," Dr. Link said. "The regulatory path is only one of the risks facing innovation, but it is often the most significant risk. As time lines have been stretched, funding has declined. I'm worried about that." Calling himself an eternal optimist, however, Dr. Link said collaboration between the FDA and industry is solid and improving. EW Monday, April 28, 2014 ASCRS Symposia by Michelle Dalton EyeWorld Contributing Writer Dr. Chambers said the issue with crosslinking is that data hasn't been submitted to meet the criteria of the FDA.

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