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The iPLEDGE program is a risk management distribution program mandated by the U.S. Food and Drug Administration (FDA) for isotretinoin, marketed as Absorica, Claravis, Amnesteem, Myorisan, and Zenatane, and sometimes referred to by its former brand name, Accutane. Isotretinoin is a prescription medication that is highly effective in treating severe acne and moderate acne that doesn't respond to other treatments, however carries a high risk of causing severe birth defects if taken during pregnancy (see Teratogenicity of isoretinoin). 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 program was designed by the Isotretinoin Product Manufacturers Group (IPMG) and its chosen vendor, Covance, under the direction of the FDA.
As of March 1, 2006, iPLEDGE patients, their doctors and their pharmacists are required by the FDA to register and use a web site in order to receive, prescribe or dispense this medication. The program has reduced exposure of pregnant women to the drug, and has also been criticized for being overly complicated.
- 1 Process
- 2 Background and history
- 3 Criticisms
- 4 References
- 5 External links
Once a doctor decides a patient is a candidate for isotretinoin, they will counsel the patient to ensure the patient understands the drug and the potential side effects. Once the patient signs the necessary paperwork, their doctor will give them a patient ID number and ID card, as well as other program educational materials. After they have been registered in iPLEDGE by their doctor, they will receive their password in the mail after 5–10 business days. Patients are classified either as females of child-bearing potential (FCBPs), females not of child-bearing potential (FnCBPs), or males.
FCBPs 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 FCBP must also take an online comprehension test to ensure she understands the requirements of the Program. Once those two items are complete, the FCBP is authorized to receive drug at an authorized pharmacy. From the date of the second (confirmatory) negative pregnancy test, an FCBP has seven days to pick up her prescription. FCBPs must see their doctor and take a pregnancy test in each subsequent month in order to get another prescription for the next 30 days.
Males and FnCBPs 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. Patients who acquire and consume isotretinoin without the care of a prescriber are putting themselves in jeopardy.
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 author of a 2002 paper from Harvard Law School wrote: "Accutane also has the potential to destroy lives. Accutane is an extremely dangerous teratogen: It can cause severe birth defects when taken during pregnancy. About one quarter of babies born who have been exposed to Accutane during gestation have major congenital deformities. Those babies born without major malformations frequently develop severe learning disabilities. A whole segment of Accutane babies do not even survive pregnancy: 40% are spontaneously miscarried." The author goes on to compare Accutane to Thalidomide.
The iPLEDGE Program was instituted as a replacement for the failed SMART program (System to Manage Accutane Related Teratogenicity). Instituted in April 2002, SMART aimed to eliminate isotretinoin-induced birth defects by preventing pregnant women from being prescribed or exposed to the drug. 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 women 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 women 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 women prescribed isotretinoin actually increased by hundreds of documented cases over the previous year, before the program was instituted. Of these cases, the majority of women 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 women reported that their physicians had attempted to downplay the risks of isotretinoin or violated the standards in other ways, such as failing to inform women they needed 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 women affected was likely far higher than the reported number.
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 to childbearing-age women in the United States. 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.
The iPLEDGE program was put into place a group formed by the companies that manufactured the drug at the time – Roche, Mylan, Barr, and Ranbaxy – called the Isotretinoin Products Manufacturing Group (IPMG); they are responsible for iPLEDGE and they hired Covance to manage it. The program launched on March 1, 2006, at the beginning of the annual meeting of the American Academy of Dermatology.
In the U.S., around 2000 women 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. After the FDA put the more strict iPLEDGE program in place for the companies marketing the drug in the US, in 2011, 155 pregnancies occurred among 129,544 women of childbearing potential taking isotrentinoin (0.12%).
Criticisms of the iPLEDGE program include the following:
Difficulty of compliance
Due to the nature of restricted distribution programs in general, and ETASU[clarification needed] REMS programs specifically, stakeholder burden has always been balanced against control and 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 jointly built by the drug manufacturers with the assistance of Covance, Inc, and approved by the FDA. 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 misses her 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.
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've become pregnant.
Requirements of the program also mandate, per FDA requirements, monthly pregnancy tests for women 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 males and non-child bearing females
The iPLEDGE Program requires the participation of both males and FnCBPs, and this has been a subject of criticism over the course of the program's lifetime. Dermatologist Ned Ryan said "They [the FDA and drug manufacturers] want a wide net, understandably. But this is completely over the top."
Participation is required to ensure that these two groups understand the basic requirements, as sharing of medication with women who can get pregnant is a real concern.
Though they must be part of the iPLEDGE Program, requirements for males and FnCBPs are more lenient than those for FCBPs. Males and FnCBPs 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 FCBPs.
Disproportionate impact on minorities and lower socioeconomic status groups
A 2019 study of patients at two academic institutions in Boston, Massachusetts demonstrated differences in delayed starting, interruption, and early termination of isotretinoin treatment course across race. Non-white patients were more likely than white patients to experience medication interruptions and early terminations and were more likely to achieve sub-optimal doses of isotretinoin. The most common cited reasons for delays were logistics associated with the iPLEDGE system, including computer issues, missed pick-up windows, and missed/delayed appointments/tests.
Criticisms of the iPLEDGE website and phone system
The program was mandated by the FDA despite criticism from practicing medical doctors that its cumbersome nature and strict deadlines can make the drug unavailable to deserving patients. In practice, the website has presented many problems to physicians; once information is entered, it can be difficult or impossible to change or correct it. If there is an error, the patient can be locked out for 30 days without being able to receive the medication. Problems are common and take days to correct. Technical assistance by phone is available via a toll free number, but trying to correct problems using the phone system can be difficult and time-consuming. Cathy Boeck, a past president of the Dermatology Nurses Association, said "Nurses are having the same frustrations as doctors regarding difficulties of getting the drug to patients and patients' complaints. It has a huge impact on resources if someone is waiting on hold with iPLEDGE and is also taking calls from patients who are upset and frustrated. That’s what we’ve heard from members."
Although the goal of the program is to prevent pregnancies of women who take the drug, male patients must also participate in anti-pregnancy restrictions, primarily due to fears that male isotretinoin users might share their prescriptions with females without their physicians' knowledge. There has been no link to birth defects from Accutane associated with males using the drug, though male sexual dysfunction has been suggested by one study. As this has not been conclusively proven, this is not acknowledged as a side effect in the official literature accompanying the medication.
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- "FDA Fails To Postpone March 1 Start Date Of iPLEDGE Program For Isotretinoin Patients". BioSpace. Retrieved 2018-12-16.
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- "iPledge REMS - Public Home Page". www.ipledgeprogram.com.
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- "Isotretinoin Update | The Dermatologist". www.the-dermatologist.com.
- WebMD Medical News: "FDA OKs Tighter Controls for Accutane." News release, John Wiley & Sons, Inc.
- WebMD Medical News: "Accutane's Pregnancy Risk: Are Women Aware?" Miranda Hitti. Oct. 14
- Robertson J, Polifka JE, Avner M, Chambers C, Delevan G, Koren G, Lavigne SV, Martinez LP, Miller RK, Carey JC (November 2005). "A survey of pregnant women using isotretinoin". Birth Defects Research. Part A, Clinical and Molecular Teratology. 73 (11): 881–7. doi:10.1002/bdra.20197. PMID 16228976.
Almost 1/4 of the women surveyed (24%; 8/34) did not recall having contraception counselling before starting their medications. Once therapy was initiated, 62% (21/34) recalled using a birth control method, but only 29% (6/21) recalled using 2 forms of birth control, as specified by the voluntary pregnancy prevention programs. Monthly pregnancy tests were not always conducted during treatment, as recalled by the surveyed women (56%; 19/34). As many as 24% (8/34) of the women surveyed recalled that they were not screened using 2 pregnancy tests before receiving a prescription, another recommendation of the programs. Only a small number of the women (30%; 6/20) in the United States recalled being enrolled in any manufacturers' voluntary pregnancy prevention survey. . . Results demonstrate that essential components of voluntary pregnancy prevention programs were not consistently followed, which resulted in fetal exposures.
- WebMD Medical News: "FDA Panel Urges Stricter Acne Drug Tracking; Women Still Having Risky Pregnancies While Taking Accutane", Feb 27, 2004
- Darves, Bonnie (March 9, 2006). "Dermatologists Frustrated With Problematic iPledge Program". Medscape.
- Kovitwanichkanont T, Driscoll T (September 2018). "A comparative review of the isotretinoin pregnancy risk management programs across four continents". International Journal of Dermatology. 57 (9): 1035–1046. doi:10.1111/ijd.13950. PMID 29508918.
- "Dermatologists Frustrated With Problematic iPledge Program". Medscape.
- Life After iPLEDGE, The Dermatologist, September 4, 2008.
- "iPledge REMS - Public Home Page". www.ipledgeprogram.com.
- "RISK EVALUATION AND MITIGATION STRATEGY (REMS)" (PDF). www.fda.gov. 2012. Retrieved 2019-07-03.
- "iPledge REMS - Public Home Page". www.ipledgeprogram.com.
- Mostaghimi, Arash; Joyce, Cara; Waul, Michael; Lu, Jessica; Xia, Fan Di; Charrow, Alexandra (2019-03-26). "Differences in isotretinoin start, interruption, and early termination across race and sex in the iPLEDGE era". PLOS ONE. 14 (3): e0210445. doi:10.1371/journal.pone.0210445. ISSN 1932-6203. PMC 6435230. Material was copied from this source, which is available under a Creative Commons Attribution 4.0 International License.
- Tirado Sánchez A, León Dorantes G (Nov–Dec 2005). "Erectile dysfunction during isotretinoin therapy". Actas Urologicas Espanolas. 29 (10): 974–6. doi:10.1016/s0210-4806(05)73379-9. PMID 16447596.
- ipledgeprogram.com The official iPledge program web site.
- REMS document
- FDA press release about the program
- Information from the CDC CDC and the March of Dimes Isotretinoin and other retinoids during pregnancy
- Medscape Medical News, Dermatologists Frustrated With Problematic iPledge Program, AAD 64th Annual Meeting. Focus session, March 6, 2006