FDA seeks more data for fluocinolone acetonide insert

Atlanta-The FDA has delayed approval of Alimera Sciences' investigational fluocinolone acetonide (FA) intravitreal insert (Iluvien) for the treatment of diabetic macular edema (DME) associated with diabetic retinopathy and requested two additional clinical trials.

The FDA issued a complete response letter (CRL) on Nov. 10 in response to Alimera's new drug application (NDA). In the letter, the FDA stated that it was unable to approve the NDA because it did not provide sufficient data to support that the insert was safe and effective in the treatment of patients with DME. The FDA further stated that the risks of adverse reactions shown for the insert in the FAME study were significant and not offset by the benefits shown in these clinical trials.

"Overall, we were surprised and disappointed with the FDA's decision on our application to market [the insert] in the United States to patients with this devastating disease," said Dan Myers, Alimera's president and chief executive officer.

The CRL also requested additional clinical data from patients who had been treated for DME with the sustained drug delivery system's inserter. In September 2011 Alimera enrolled the first patient in a physician utilization study of the intended commercial insertion device, a study requested by the FDA to ensure that patients understood the instructions for using the inserter. Nearly 60 patients have been enrolled in the study; those who have been screened and scheduled for the insert will be allowed into the study. It will then be suspended pending the outcome of the meeting between Alimera and the FDA, expected to take place this month.

During that meeting, Alimera executives will learn in more detail what the FDA expects concerning the additional clinical trials and what specific aspects of the safety profile have concerned the regulators. It would not be feasible for the company to pursue new trials similar in size and cost to the FAME study, Myers said.

If that is the FDA's position, Alimera may look at other indications for the insert for which it has the rights, he added.

The CRL sent in November was the second Alimera has received in connection with its NDA for the insert. The FDA issued the first CRL in December 2010, 6 months after Alimera submitted the NDA with data through month 24 of the FAME study. In that CRL, the FDA requested analyses of safety and effectiveness data through month 36 of the study; this information was provided in Alimera's May 12, 2011 response.

The response was classified as a Class 2 resubmission and resulted in a 6-month review period culminating with the most recent CRL.

The FAME Study, which cost about $75 million, consisted of two 3-year phase III pivotal clinical trials (Trial A and Trial B) of the FA insert for the treatment of DME. Patients were randomly assigned to either high-dose FA, low-dose FA, or control treatment.

The study's primary efficacy endpoint was the difference in the percentage of patients whose best-corrected visual acuity improved by 15 or more letters from baseline at month 24 between the treatment and control groups.

Data through month 36 for the Full Analysis Set in Trial A demonstrated statistically significant therapeutic effects of 28.9% at month 30 (p = 0.011) and 28.4% at month 33 (p = 0.042) in the FA group compared with less than 17% of the control group.

Similar results were reported in Trial B. The therapeutic effect was maintained through month 36, although the p value increased to 0.106 because a higher percentage of patients in the control group (18.9) gained 15 or more letters.

Safety was assessed among those patients treated with the insert who were in a subgroup of patients with DME for 3 years or more. IOP increases to 30 mm Hg or greater at any time point were seen in 14.8% of these patients by month 36, compared with 18.3% in the full FA-treated patient population. The incidence of cataracts among patients who were phakic at the time of enrollment was 86% at month 36, with 85% undergoing a cataract operation, compared with 80% and 74.9%, respectively, in the full patient population.

Myers said that that Alimera has always been "up front" about the side effect profile associated with the insert in the study.

"Given the efficacy data that we had, we felt it was very manageable," he noted.