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The iPLEDGE program is a mandatory distribution program in the United States for isotretinoin (commonly sold under the trade names Claravis, Absorica, Amnesteem, Myorisan, Sotret or Zenatane), intended to prevent the use of the drug during pregnancy due to the high risk of birth defects (see Teratogenicity of isoretinoin). As of March 1, 2006, patients and their doctors and pharmacists are required by the U.S. Food and Drug Administration (FDA) to register and use a web site in order to receive this medication.
- 1 Overview and Process
- 2 History
- 3 Criticisms
- 4 References
- 5 External links
Overview and Process
The iPLEDGE Program website (www.ipledgeprogram.com) and automated phone system are part of the iPLEDGE Program, which is an FDA-mandated REMS (Risk Evaluation Mitigation Strategy) program designed to mitigate the risks associated with taking isotretinoin.
The goals of the isotretinoin risk evaluation and mitigation strategy are: 1. To prevent fetal exposure to isotretinoin 2. To inform prescribers, pharmacists, and patients about isotretinoin’s serious risks and safe-use conditions
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've been registered in iPLEDGE by their doctor, they'll 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) pregnancy test, the FCBP must also take an online comprehension test to ensure they understand 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) pregnancy test, FCBPs have 7 days to pickup their 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 dates of their office visit to pickup their prescriptions - after that point they have to see their doctor for another 30-day prescription.
Before dispensing isotretinoin, the pharmacist will check the iPLEDGE Program website to ensure the patient is authorized to receive 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 that insist upon dispensing 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 the be an option when nothing else has worked.
The iPLEDGE Program (an FDA-mandated REMS Program - see below) was instituted by the FDA on March 1, 2006 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.
How did REMS come to be?
"Public outcry over revelations of unforeseen risks from trusted medicines has been the historical driver for incremental advancements of the Food, Drug, and Cosmetic Act. Moving from a toehold in drug safety in the 1906 Act, FDA gained expanded public health responsibilities relating to the safety, effectiveness, and labeling of medicines as a result of reactive legislation to the 1938 sulfanilamide and 1951 thalidomide tragedies. Intermittent drug-specific safety issues dogged the agency in the 1980s-1990s (eg, aspirin, phenylpropanolamine, "fen-phen," etc.).
A concurrent issue of high rates of liver toxicity for newly approved but withdrawn medicines resulted in FDA's creation of a Task Force on Risk Management Committee, which framed the conceptual basis of a systems approach to modern risk management of drug/biologic safety. Thus, in 2004, when a chasm in consumer confidence widened abruptly with challenges to rofecoxib, valdecoxib, and salmeterol, the ground was amply prepared for the 2007 negotiated reauthorization of the Prescription Drug User Fee Act that gave FDA substantial new authority in the postmarketing phase of drug safety.
The FDA's earlier approaches to risk management used Risk Minimization Plans (RiskMaps) to help curb unsafe prescribing and self-care practices by physicians and patients, respectively. RiskMaps are now subsumed under the REMS regulatory infrastructure. Isotretinoin is a prominent example of a medicine with a comprehensive pre-FDAAA RiskMap (iPledge) for pregnancy prevention in females, with a very complex integrated array of requirements (such as monthly pregnancy tests a precondition of initial and active registry, and prescriber registration) for the prevention of fetal exposure/pregnancy in patients taking isotretinoin. A sponsor report in February 2009 indicated that 40 physicians were terminated from iPLEDGE, mainly for misrepresenting information regarding the date of the required pregnancy test and gender. Most were voluntarily reported by pharmacists and patients.
This comprehensive systems-based approach to risk management of isotretinoin predated FDAAA and helped set the stage for legislation that would allow the agency to broaden its program through documentable postmarketing safety programs. With informed consent of patients and protocol-based documentation features, the early iPLEDGE Program and more recent complex REMS are essentially phase IV surveillance studies and de facto regulate the practice of medicine.
REMS now provide FDA with a publicly acknowledged and visible scheme comprised of an escalating set of more restrictive safeguards to help ensure the public's well being. With the increasing ability to field extremely large studies to assess risks and benefits of drugs in the pipeline and those already marketed, there is the parallel increase in the sensitivity of such studies to identify very small, albeit highly serious, risks from medicines. Without a comprehensive strategy to allow FDA to gain control of mitigating risk, patients could be needlessly hurt, pharmaceutical companies would be disadvantaged by losing products through withdrawals, physicians would potentially have less protection in liability cases, and FDA would be seen as not doing its job."
Failure of 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.
Introduction of 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.
Criticisms of the iPLEDGE program include the following:
Difficulty of compliance
Due to the nature of restricted distribution programs in general, and ETASU 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 were concerned that this very effective drug was being 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 the initial issues with the system have subsided, the nature of the restrictive distribution program continues to cause inconvenience for some patients. For example, if there is a problem with the data a patient or prescriber enters, that patient may be locked out of the system, unable to obtain drug, for that 30 day cycle. Additionally, if a patient misses her 7-day prescription window, that patient must return to the prescriber for another pregnancy test before being able to get drug for that month. This return to the doctor, of course, can be inconvenient and costly.
The duality of prescribers' feelings about isotretinoin can be seen in the two paragraphs below, and also explain why the burden associated with the Program is warranted, given the risks to patient / fetal safety.
"Many reports and studies criticizing the drug’s negative side effects have been published over the years, with strong language both for and against use of the medication. 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.
On the other side of the argument, dermatologists praise the drug 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.”
Some patients feel that the requirements to take monthly pregnancy tests and enter information about contraceptive choices constitute an unreasonable instrusion, 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 includes a privacy statement, which discusses what information is collected, how it is used, and where questions can be directed.
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. 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.
Criticisms of the iPLEDGE website
Some criticisms of the iPLEDGE website include the website provides no information about who administers the site or how patients' private information is secured.
The program was mandated by the FDA despite criticism from practicing medical doctors that its cumbersome nature would 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 is locked out for 30 days and cannot receive the medication. Problems are common and take days to correct. Technical assistance by phone is available via a toll free number.
Although the goal of the program is to prevent pregnancies, male patients must also participate in the iPLEDGE Program, primarily due to the fact that males in the Program will share their isotretinoin with females who are not in the Program. 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.
- "Ipledgeprogram.com Site Info". Alexa Internet. Retrieved 2014-04-01.
- 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, Julia; et al. (November 2005). "A survey of pregnant women using isotretinoin". Birth Defects Research (Part A): Clinical and Molecular Teratology 73 (11): 881–887. doi:10.1002/bdra.20197. PMID 16228976. Retrieved 2009-02-07 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
- Tirado Sánchez A; León Dorantes G. (Nov–Dec 2005). "[Erectile dysfunction during isotretinoin therapy]". Actas urologicas españolas. 29 (10): 974–6. PMID 16447596.
- [Erectile dysfunction during isotretinoin therapy] 29 (10). 2005. pp. 974–6. 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 Dimesabout Accutane and birth defects
- Medscape Medical News, Dermatologists Frustrated With Problematic iPledge Program, AAD 64th Annual Meeting. Focus session, March 6, 2006
- The iPLEDGE Program Patient Introductory Brochure