ALLERGAN’s OCUFEN POST-OP CYSTOID MACULAR EDEMA DATA NEEDS MORE ANALYSIS OF DROPOUTS BEFORE APPROVAL, FDA OPHTHALMIC DRUGS SUBCOMMITTEE CONCLUDES OCT. 27

Allergan's Ocufen data do not support a new indication for prevention of postoperative cystoid macular edema (CME) without further analysis, FDA's Anti-Infective Drugs Advisory Committee's Subcommittee on Ophthalmic Drugs concluded by a three-to-one vote on Oct. 27. Allergan consultants presented results of two placebo- controlled trials designed to show whether treatment with Ocufen (flurbiprofen .03% eye drops) four times daily following cataract surgery for up to four months would reduce the incidence of cystoid macular edema. CME, a swelling around the surgical scar, occurs four to eight weeks following surgery in 20%-30% of patients. Endpoints were angiographic CME (i.e., swelling detected by angiography) and clinical CME (i.e., swelling detected by angiography where patients have vision impairment below 20/40). The company also presented contrast sensitivity data. Allergan's proposed indication was for "management of postoperative CME and prevention of associated visual dysfunction." Members of the subcommittee appeared to agree that Allergan's clinical trials in support of the indication showed sufficient benefit for approval. However, they felt that the company needed to provide an analysis of patients who dropped out of the trials. Citing the lack of dropout analysis, Committee Chairman Thomas Beam, MD, Buffalo Veterans Administration Medical Center, said Allergan "is missing a small piece of data analysis which unequivocally changed my opinion." The two trials enrolled a total of 1,154 patients who agreed to return for seven follow-up visits over eight months following cataract surgery. Patients were given angiograms at baseline, visit five (day 21-60) and visit seven (day 121-240). Due to the difficulty of accruing patients with such a protocol, the trials took over six years (1985-1991) to conduct, Allergan said. FDA medical reviewer Tony Carreras, MD, summarized the trials for the committee. Drug treatment showed "a smaller rate of angiographic CME" and a "less substantial but smaller rate of clinical CME at visit five but not at visit seven," Carreras said. Patients showed an improvement in contrast sensitivity in one of the trials but "no visual acuity advantage at either visit five or seven." Carreras asked if that were "sufficient to warrant the use of the drug" in postoperative patients. There was a "subset of patients who clearly...showed sufficient benefit" to warrant approval, Beam responded. The key issue in the committee's vote against approval was raised by committee consultant Michael Belin, MD, Albany Medical College. He noted that the dropout rate in the trial (16.5%) was approximately the same as the rate of clinical CME. "If you have a higher complication rate than the rate of disease, no one is going to give the drug," Belin said. Allergan responded that most dropouts were for reasons unrelated to the study drug or surgery complications; Belin, however, wanted a complete analysis. "Most of this can probably be done internally with the FDA," Belin said. Beam told FDA Medical Imaging, Surgical and Dental Drug Products Division Acting Director Wiley Chambers, MD, that "I'll leave this to your discretion whether you want to follow up with this at a subsequent subcommittee meeting or whether you want to take this recommendation internally and deal with it at the agency." The new indication would dramatically expand Ocufen's market potential. Allergan consultant Mark Abelson, MD, estimated that, with over 1 mil. cataracts operations performed a year and a 20%- 30% incidence of CME, the condition could affect 300,000 people annually. He estimated that the "economic liability" of the disease is at least $120 mil. Ocufen was approved for short-term use to reduce intraoperative myosis on Dec. 31, 1986. Allergan submitted an NDA (19-404) for the CME indication in February.