The iPLEDGE program is a program by the U.S. Food and Drug Administration (FDA) intended to manage the risk of birth defects caused by isotretinoin, a prescription medication used for the treatment of acne. Patients, their doctors and their pharmacists are required by the FDA to register and use the iPLEDGE web site in order to receive, prescribe or dispense isotretinoin.
Isotretinoin carries a high risk of causing severe birth defects if taken during pregnancy (see Teratogenicity of isotretinoin) and the goals of the iPLEDGE REMS (risk evaluation and mitigation strategy) program are to prevent fetal exposure to isotretinoin and to inform prescribers, pharmacists, and patients about isotretinoin's serious risks and safe-use conditions.
The iPLEDGE program was put into place by a group formed by the companies that manufactured the drug at the time called the Isotretinoin Products Manufacturing Group (IPMG) under the direction of the Food and Drug Administration. The program launched on March 1, 2006, at the beginning of the annual meeting of the American Academy of Dermatology.
According to a study published in 2011, the program has not significantly reduced exposure of pregnant people to the drug in comparison to the previous SMART program. It has been criticized for being overly complicated and difficult for prescribers, pharmacists and patients to navigate successfully.
Process Once a prescriber decides a patient is a candidate for isotretinoin, they counsel the patient to ensure they understand the drug and the potential side effects. Once the patient signs the necessary paperwork, their prescriber will give them a patient ID number, ID card, and program educational materials. After a patient has been registered in iPLEDGE by their prescriber, they receive their password in the mail within 5–10 business days.
iPLEDGE originally classified patients as females of child-bearing potential (FCBPs), females not of child-bearing potential (FnCBPs), or males. Effective December 13, 2021 iPLEDGE switched to gender neutral categories: patients who can get pregnant and patients who cannot get pregnant.
Patients who can get pregnant are required to pick and use two birth control methods (abstinence included), and must take doctor-administered pregnancy tests in two consecutive months. After the second (confirmatory) negative pregnancy test, the patient must also take an online comprehension test to ensure they understand the requirements of the Program. Once those two items are complete, the patient is authorized to receive drug at an authorized pharmacy. From the date of the second (confirmatory) negative pregnancy test, a patient who can get pregnant has seven days to pick up their prescription. They must see their doctor and take a pregnancy test in each subsequent month in order to get another prescription for the next 30 days.
Patients who cannot get pregnant must see their doctor every month, but don't have to take the pregnancy or comprehension tests. They have 30 days from the date of their office visit to pick up their prescriptions. After that point they have to see their doctor for another 30-day prescription.
Before dispensing isotretinoin, the pharmacist must check the iPLEDGE Program website to ensure the patient is authorized to receive the drug. Isotretinoin may only be dispensed at authorized US pharmacies that are registered with the iPLEDGE Program, and FDA has taken action against Canadian and internet pharmacies which dispense isotretinoin outside of the iPLEDGE Program.
The typical course of isotretinoin treatment will last 4–5 months, and is generally considered to be an option when nothing else has worked.
Background and history
Some dermatologists have praised isotretinoin for its ability to treat severe acne, with current research calling it "a drug of choice" with "immense promise ... in reducing dermal irritation and increasing the therapeutic performance, thus resulting in an efficacious and patient-compliant formulation". However, there have also been many reports and studies criticizing the negative side effects of isotretinoin have been published over the years.
The iPLEDGE Program was instituted as a replacement for the failed SMART program (System to Manage Accutane Related Teratogenicity).WebMD Medical News: "FDA OKs Tighter Controls for Accutane." News release, John Wiley & Sons, Inc. Instituted in April 2002, SMART aimed to eliminate isotretinoin-induced birth defects by preventing exposure to the drug during pregnancy. The program mandated two consecutive negative pregnancy tests, birth defect risk counseling and a pledge to use two forms of contraception when engaging in intercourse for all people assigned female at birth of childbearing age seeking an isotretinoin prescription. A voluntary registration program called The Accutane Survey was also established. However, no effort was made to verify the compliance of doctors and pharmacists, only a small percentage of people registered in the survey, and isotretinoin's reputation as an acne wonder drug continued to fuel demand for new prescriptions, an increasing number of which were being written and dispensed for relatively minor cases of acne vulgaris without proper screening, supervision or evidence that less risky medications had first been attempted.
Failure of the previous system In 2003, a first-year review of SMART compliance conducted by the pharmaceutical industry revealed that the number of pregnant people prescribed isotretinoin actually increased by hundreds of documented cases over the previous year, before the program was instituted. Of these cases, the majority underwent abortions—either spontaneous or elective—with a handful of children reported to be born with typical isotretinoin-induced birth defects. When surveyed, many pregnant people reported that their physicians had attempted to downplay the risks of isotretinoin or violated the standards in other ways, such as failing to inform them of the need to use two forms of birth control or allowing them to substitute a single, less-accurate urine pregnancy test conducted in the doctor's office for the two laboratory-conducted blood pregnancy tests mandated by SMART. The FDA also concluded that, considering the voluntary nature of the reporting program and lack of mandatory record-keeping, the actual number of pregnant people affected was likely far higher than the reported number.WebMD Medical News: "FDA Panel Urges Stricter Acne Drug Tracking; Women Still Having Risky Pregnancies While Taking Accutane", Feb 27, 2004
Mandatory reporting and verification The report led to SMART being dismissed as "a total failure", with the FDA quickly moving to halt the downward slide with a stricter mandatory registry system to document and verify all isotretinoin prescriptions written or dispensed in the United States.WebMD Medical News: "Accutane's Pregnancy Risk: Are Women Aware?" Miranda Hitti. Oct. 14 This was a feature originally included in the plan for SMART recommended by the original FDA advisory panel and wholeheartedly endorsed by the pharmaceutical manufacturers, but removed due to concerns that political opposition from lobbying groups would delay the program's implementation. Although eventually resolved, the older concerns proved valid in 2003 when the launch of iPLEDGE was held up for three years while objections from women's rights, patient's rights, physician's rights and pro-choice lobbyists were debated in committee.
In the U.S., around 2000 people became pregnant while taking the drug between 1982 and 2000, with most pregnancies ending in abortion or miscarriage. About 160 babies with birth defects were born. In 2011, after the FDA put the more strict iPLEDGE program in place, among 129,544 patients taking isotrentinoin who have the capacity to become pregnant, 155 pregnancies occurred (0.12%).
Criticisms Criticisms of the iPLEDGE program include the following:
Difficulty of compliance When the Program launched in March 2006, there were many complaints about how difficult it was to use the system. Launch and pre-launch difficulties were common with the system. Glitches with the website and long hold times were rampant at the time, and became a focus of physician and patient ire. Physicians have continued to be concerned that this very effective drug is made difficult to obtain due to a relatively small proportion of potential birth defects.
Though prescriber and pharmacy populations have become more familiar with the requirements of the iPLEDGE Program over the years, and some of the initial issues with the system have subsided, the nature of the restrictive distribution program continues to cause inconvenience, added expenses, and interruptions in the course of treatment. For example, if there is a problem with the data a patient or prescriber enters, the patient may be locked out of the system, unable to obtain the drug, for that 30-day cycle. Additionally, if a patient who can become pregnant misses their 7-day prescription pick-up window, the patient must return to the prescriber for another pregnancy test before being able to get the drug again. This return visit to the doctor, of course, can be inconvenient and costly. To minimize the number of necessary visits to the doctor, a patient would want to schedule their appointment near the end of a 30-day period, but then must pick up the medicine quickly to avoid being blocked out of the system and running out of the medication. In 2008, dermatologist Robert Greenburg said "For a program to be so inflexible that it doesn't take into consideration the holiday or a patient's extenuating circumstances is such an impediment. It happens often that the 30-day window runs into the weekend when offices are closed. This [iPLEDGE] isn't the way things are done in the real world." "Why is iPLEDGE so complicated? Clearly, it's for political reasons," said Greenberg, citing political opposition to abortion and his impression that morality has guided the policy development more than medical science and evidence of effectiveness.
Privacy intrusion
Some patients feel that the requirements to take monthly pregnancy tests and enter information about contraceptive choices constitute an unreasonable intrusion, and feel that's too high a price to pay to gain access to this drug. Additionally, maintenance of a pregnancy registry is part of the Program, though participation in the registry is voluntary for those patients who might have become pregnant.
Requirements of the program also mandate, per FDA requirements, monthly pregnancy tests for patients who may become pregnant.
The website does include a privacy statement, which discusses what information is collected, how it is used, and where questions can be directed.
Required participation of patients who cannot become pregnant
The iPLEDGE Program requires all patients to participate whether they can become pregnant or not, and this has been a subject of criticism over the course of the program's lifetime.
Program administrators say all patients must participate as they are concerned about the potential sharing of medication with people who can become pregnant. Dermatologist Ned Ryan said "They [the FDA and drug manufacturers] want a wide net, understandably. But this is completely over the top."
Though they must be part of the iPLEDGE Program, requirements for patients who cannot become pregnant are more lenient than requirements for patients who can become pregnant. Patients who cannot become pregnant do not need to take either pregnancy or comprehension tests on a monthly basis, and their prescription window is 30 days from the date of the office visit, rather than seven days as it is with patients who can become pregnant.
Economic burden on patients who can become pregnant