SILVER SPRING, MD. – The iPLEDGE risk management program for isotretinoin has reduced fetal exposure to the teratogen but still needs to be tweaked to reduce burdens on physicians and improve patient access, advisers to the Food and Drug Administration said Dec. 1.
The agency is required by law to bring at least one drug a year to its Drug Safety and Risk Management Advisory Committee to determine if the product’s risk management evaluation and mitigation strategy (REMS) is ensuring safe use. Isotretinoin was chosen for that exercise this year.
Three versions of isotretinoin currently are on the market: Amnesteem, Sotret, and Claravis. The makers of those products said at the meeting that they were already planning on making changes to the iPLEDGE program in 2012. It’s not clear whether the panels’ suggestions would be incorporated then.
"I’m exceedingly impressed with what has evolved over time," said Dr. Wilma F. Bergfeld, professor of dermatology and pathology at the Cleveland Clinic and a temporary voting panelist on the Dermatologic and Ophthalmology Drugs Advisory Committee. She said that that it seemed that manufacturers, the FDA, physicians, and pharmacists were working together to make the program even better. "With everyone working at this, I believe the risk will go down."
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Dr. Andrea Zaenglein discusses the burden of the iPLEDGE program.
Dr. Andrea Zaenglein of the departments of dermatology and pediatrics at Pennsylvania State University at Hershey said that while she was personally happy with the iPLEDGE program, it did constitute somewhat of a burden for physicians.
She said she spends at least 30 minutes counseling patients at the initial visit and then at least 15-20 minutes at each subsequent visit. Dr. Zaenglein, who spoke on behalf of the American Academy of Dermatology Association during the public portion of the meeting, said that the organization wanted to have more physicians participate in the ongoing evaluation of iPLEDGE. And, she said, the AADA hoped to have men and women of non–childbearing potential taken out of the registration process.
Dr. Robert A. Silverman, past president of the Society for Pediatric Dermatology, said that Dr. Zaenglein’s estimate on time spent counseling was conservative. He said he counsels patients over two or three extended visits, and that often he holds separate meetings with parents.
"After-hours discussion in my practice is not uncommon," added Dr. Silverman of Georgetown University, Washington. Still he said, isotretinoin "is a miracle drug that saves lives."
The dermatologists’ concerns about physicians’ burdens were echoed by the FDA panelists.
The panelists noted that they were especially worried about what seemed to be a lack of understanding among patients and even physicians about birth control. Several wanted to see a clearer, more concrete presentation to patients on the relative merits and effectiveness of various contraceptive methods. They also asked for more data on why pregnancies were still occurring. And several panel members suggested that men and women who are shown to not be of child-bearing potential be removed from most of the restrictions imposed by iPLEDGE.
For the year ending February 2011, 569,385 women of childbearing potential, 45,484 women of non–childbearing potential, and 620,012 men had enrolled in iPLEDGE since its inception in 2006.
The committee was first asked to whether iPLEDGE is continuing to assure the safe use of isotretinoin. Overall, there have been 836 pregnancies since 2006; of those, 400 were terminated and 282 patients were lost to follow-up. A total of 45 live births were recorded; of those, 8 were children born with congenital anomalies.
In the year ending February 2011, there were 155 pregnancies, a decline from 186 the previous year, and 190 in 2008. Dr. Eric Davis, director of medical services for Mylan Pharmaceuticals, said that the pregnancy rate for iPLEDGE patients was 1.27/1,000, as compared with the 51/1,000 rate of unintended pregnancies in the general U.S. population.
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The FDA panel meets to evaluate isotretinoin.
James Shamp, director of risk management programs at United BioSource Corp., which helped develop iPLEDGE, said that analysis of program data had determined that some physicians were erroneously classifying women as being of non-childbearing potential. To mitigate against such errors, the iPLEDGE online system next year will include a "wizard" that will classify women as of childbearing potential or of non–childbearing potential based on a series of responses from the prescriber.
The panelists were also asked whether iPLEDGE was "unduly burdensome" for patients. FDA officials said that after iPLEDGE was introduced in 2006, there was a 29% drop in use by men and a 55% drop in use by women. Use among men recovered to pre-iPLEDGE levels within 7 months, but it took almost a year for usage to recover among women, according to Marta Wosinska, an analyst at the FDA Center for Drug Evaluation and Research. She said that iPLEDGE may have negatively affected patient access, but that the program also probably caused physicians to make more clinically appropriate prescribing decisions in certain cases.