It’s been 13 years since the U.S. Food and Drug Administration took a bold step to prevent birth defects caused by the only drug that can cure severe acne.
By MARIE MCCULLOUGH
The Philadelphia Investigator
(TNS) – It’s been 13 years since the U.S. Food and Drug Administration took a bold step to prevent birth defects caused by the only drug that can cure severe acne.
Women were still getting pregnant while taking isotretinoin, under the brand name Accutane, despite two decades of restrictions and precautions. So in 2006, the FDA imposed iPLEDGE, a rigorous registry program, which dermatologists immediately called a cumbersome and confusing mess.
The iPledge brochures indicate that registry data is used to assess the effectiveness of the program and improve it.
But the FDA has not publicly shared this data or indicated whether it believes iPledge has been successful.
Now a new study concludes it doesn’t.
Exploring the FDA’s public database of drug-related “adverse event” reports, researchers found 6,740 pregnancies in women on isotretinoin from 1997 to 2017.
iPLEDGE did not reduce the rate of fetal exposure more than the previous pregnancy prevention program. And while the absolute number of pregnancies per year has declined from a peak of 768 in 2006, it plateaued in 2011. Each year since then, around 200 to 300 isotretinoin users have become pregnant, according to the study.
“iPLEDGE may not deter pregnancy,” said John Barbieri, dermatology researcher at the University of Pennsylvania, co-author of the study published last month in JAMA Dermatology. “The flip side is that we find that iPLEDGE can have the unintended consequence of discouraging use by those who need it.”
Meagan Fox, 26, a beautician from the Denver suburbs who runs the Girls Helping Girls with Accutane Facebook group, was not surprised by the results.
Last year, while taking isotretinoin for five months to get rid of her cystic acne, Fox made a commitment – as iPledge requires – to using two forms of birth control. Even though she already had a 99% effective contraceptive implant, she and her longtime boyfriend added condoms.
But some women are exempt from this requirement. All they have to do is promise not to have sex.
“To make iPledge more effective, get rid of the abstinence option first,” Fox said. “It just doesn’t work.”
Some doctors fill this iPLEDGE gap.
“I don’t consider abstinence to be a valid form of birth control,” said Nazanin Saedi, dermatologist and laser surgeon at Thomas Jefferson University Hospital. “I tell them birth defects can be horrible. I would sleep better at night knowing that you are using some form of birth control.”
Asked for comment, the FDA sent an email: “Is the information in the pregnancy register confidential?”
The debut in 1982 of Accutane, a derivative of vitamin A, was a turning point in dermatology. Suddenly, a common, stubborn illness that was healing both physically and emotionally could be cured, or nearly so, usually with tolerable side effects like temporary chapped lips and peeling skin. (Accutane developer Hoffmann-la Roche sold the product to 13 million people before quitting in 2009, ceding the market to generic versions. Yet the well-known name persists.)
Isotretinoin has triggered depression in some users, but this could be monitored during the five or six months of treatment.
Unintentional pregnancies were a bigger problem. Most of them ended in abortion or miscarriage, but about 1 in 4 babies born had brain, heart or facial deformities, research shows. Even brief exposure to the drug could be devastating.
Given the fallibility of humans – and the most commonly used birth control methods – the manufacturer, doctors and regulators have recognized that it would be impossible to eliminate the risk entirely.
But it was clear that many doctors and patients were breaking guarantees such as pregnancy tests and contraceptive advice.
A Roche survey of 300,000 women treated in the 1990s found that 23% had never signed a consent form, 25% had not had an initial pregnancy test, and that a third of women who had had tests had started the drug without results. A government study of 14 women who got pregnant found that eight had had sex without birth control and two had gotten the drug from friends. One of them didn’t even have acne; she just skipped a few capsules before her period to avoid oily skin.
iPledge aimed to make women understand the dangers and tackle inappropriate access.
Like the previous pregnancy prevention program, iPledge limits patients to a 30-day supply of isotretinoin at a time. It requires two negative laboratory pregnancy tests before starting treatment, monthly pregnancy tests and doctor visits, and two forms of contraception or abstinence.
But iPledge, developed by regulators and manufacturers, goes further. It has a computerized deadline registry system that requires careful coordination between physicians, patients and pharmacists. Each month, the physician’s office and the patient must document compliance, online or over the phone. If there is a misstep, the patient is “stuck” and must either skip a month of treatment or scramble to keep the system happy by calling the toll-free number.
The prescription, for example, must be picked up within seven days of the negative pregnancy test or the pharmacist cannot dispense it. “If your 7-day prescription window expires before you get your prescription,” the patient manual states, “you must repeat the requirements of the program.”
Women who cannot get pregnant and men have milder conditions, but still need to register and have monthly doctor visits.
A study of 418 patients found that logistical problems with iPledge led 30% of white patients and 44% of non-white patients to delay treatment, interrupt it or stop prematurely. Lead author of the study, Harvard Medical School dermatologist Arash Mostaghimi, was part of the new pregnancy research.
Try to give incentives
Although the FDA declares the iPLEDGE data confidential, the four-year figures – 2006, 2008, 2009 and 2010 – were presented publicly at an advisory committee meeting in 2011.
The new study used this data, along with the adverse event reports, to calculate the rates of pregnancies, abortions and fetal malformations for those four years.
The risk of pregnancy ranged from 0.65% in 2006 (768 pregnancies out of 117,784 women) to 0.33% in 2009 (388 pregnancies out of 115,925 women). This was not less than the 0.29% rate calculated by a study of the previous pregnancy prevention program, called SMART (System to Manage Accutane Related Teratogenicity).
The new study found that the risk of fetal malformations was much lower than the 18-28% estimated by previous research, but that could be due to incomplete reports in the FDA’s Adverse Events Database. A total of 210 fetal malformations were reported from 1997 to 2017.
“The numbers are still unacceptable,” said Rahul Gupta, chief medical officer of March of Dimes, who lobbied for iPledge.