It’s been 13 years since the United States 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. Thus, in 2006, the FDA imposed I promise, a rigorous registry program that 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 no.
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.
The iPledge effort 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 study published last month in JAMA Dermatology. “The flip side is that we find that I promise may have the unintended consequence of discouraging use by those who need it.
Meagan Fox, 26, a beautician from the Denver suburbs who moderates the Facebook group Girls helping girls with Accutane, 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 are closing this iPledge loophole.
“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: “The information in the pregnancy registry is confidential… The iPledge program is robust when implemented as designed.
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, with usually tolerable side effects such as 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 taken an initial pregnancy test, and a third who had been tested 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 crack down on 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 time-based computerized 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 seven-day prescription window expires before you get your prescription,” the patient manual states, “you must repeat the requirements of the program.”
“It happens all the time,” Saedi told Jefferson. “I understand why it’s so tightly regulated, but now that we’re 13 years away, there should be a way to streamline and improve it.”
Women who cannot get pregnant and men have milder conditions, but still need to register and have monthly doctor visits.
Barbieri, at Penn, said monthly dates often conflict with jobs, school, summer camp, travel – in short, life.
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.
Although the FDA says iPledge’s data is 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 abnormalities 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 March of Dimes chief medical officer Rahul Gupta, who lobbied for iPledge. “The study is a good time to go back and reassess the program and determine what is the most prudent approach for these women while taking this drug.”
To that end, the American Academy of Dermatology recently formed a task force that plans to make recommendations to the FDA later this year. A member, Laura K. Ferris of the University of Pittsburgh Medical Center, has long advocated counseling and incentives to get women to use near-perfect contraceptive methods, namely the IUD or the contraceptive implant. (Under the Affordable Care Act, all methods must be covered by no-cost reimbursable insurance.)
“Give them incentives,” Ferris said. “We could tell them, ‘If you use one of these forms, you don’t have to use condoms. One shape is enough. And we could reduce the frequency of pregnancy tests, maybe every two months.
Barbieri and his co-authors suggest giving emergency contraception, the morning after pill, along with prescriptions for isotretinoin, and doing clinical studies to see which strategies work best.
“I think we have opportunities to use what we have learned to be more effective in reducing pregnancies,” said Barbieri.