Accutane (Isotretinoin) entered the market in the US in 1982, and has been at the center of one firestorm after another ever since. It was never intended to treat a large number of patients. The FDA approved the drug for the treatment of severe nodular cystic acne, a type of acne that is painful, disfiguring, and will not respond to other forms of treatment.
The FDA approved labeling specifically points out that the drug is not to be considered a treatment of first choice:
"Because of significant adverse effects associated with its use, Accutane should be reserved for patients with severe nodular acne who are unresponsive to conventional therapy, including systemic antibiotics."The original labeling issued in 1982, designated the drug as Category X, meaning it was to be avoided by all pregnant women. Yet by 1983, babies were being born with birth defects to mothers who used the drug during pregnancy.
Alarmed by these reports, in September 1983, the non-profit consumer advocacy group, Public Citizen, submitted a petition to the FDA requesting patient package inserts and a black box warning label be added to Accutane describing the risk of birth defects and mental retardation.
Looking back, Public Citizen has been warning the FDA about the risks of serious harm to fetuses exposed to Accutane for more than 20 years. In 1984 the group sent a letter to the FDA advocating for improved pregnancy surveillance and lower dosing regimens.
During an FDA Advisory Committee meeting in 1988, the group described isotretinoin as an imminent public health hazard and urged the panel to remove the drug from the market unless tighter and effective restrictions were implemented.
The next year the group testified again and asked the FDA to withdraw isotretinoin from the market unless the previously proposed restrictions were adopted immediately.
In 1989, the CDC testified before an FDA Advisory Committee, and stated that the birth of babies with defects caused by fetal exposure to Accutane was unnecessary and called the FDA's decision to allow the marketing of Accutane, a "failed regulatory experiment."
At a December 11, 2002 House Oversight and Investigation Subcommittee hearing on the Safety Issues Relating to Accutane, internal documents from the nation's regulatory agencies were placed in the record that showed public health officials had been expressing serious concerns about Accutane and birth defects for well over a decade.
For instance, a 1990 internal FDA memo stated, "Accutane poses an imminent hazard to public health, and as such should be withdrawn immediately from the market."
A 1990 report by the FDA said, "The magnitude of fetal injury and death has been great and permanent, with 11,000 to 13,000 Accutane-related abortions and 900 to 1,100 Accutane birth defects."
In August 1997, the FDA issued a warning letter to Roche for failing to submit serious adverse event reports in a timely manner and Roche claimed its computer systems were responsible for delays of up to eight years in complying with the law.
A February 1998 FDA memo stated that Roche "had not acted in good faith to truly and accurately answer questions relating to Accutane use in women and pregnancy exposure."
The memo goes on to recommend "active consideration of removal of Accutane from the market."
A 1998 letter to the FDA from an official at the Centers For Disease Control compared Accutane to the infamous cancer and leprosy drug, Thalidomide, known for causing of birth defects, and stated, "we simply need to remove the drug from the market."
In response to calls for the withdrawal of Accutane, Roche proposed a patient education program on the risk of birth defects, that included patient materials and informed consent forms for women to sign before receiving the drug.
In September, 2000, because the number of prescriptions to women of child-bearing age had tripled from 70,000 a year in 1989, to almost 210,000 in 1999, there was more concern over the increasing number of pregnant women exposed to the drug so FDA's Dermatologic and Ophthalmic Drugs Advisory Committee held a meeting to discuss what measures might help prevent further fetal exposure.
Public Citizen once again testified at the hearing and recommended that a Patient Medication Guide be issued and again urged the FDA to remove Accutane from the market unless restrictions were implemented and proven to be effective.
As a result of recommendations made by the Advisory Committee following the hearing, Roche agreed to develop a program designed to prevent pregnancies in women using Accutane.
The "System to Manage Accutane Related Teratogenicity," or SMART program, was implemented in April 2002, and required women to have 2 pregnancy tests before starting on Accutane, to get a pregnancy test each month before refilling a prescription, to receive counseling on birth control, and to agree to use two forms of birth control simultaneously while using Accutane.
The Adverse Event Reporting System (AERS) is a computerized database of post-marketing adverse events for all approved drugs, designed to support the FDA's post-marketing safety surveillance program.
The reports in AERS are evaluated by agency reviewers in the Center for Drug Evaluation and Research (CDER) and the Center for Biologics Evaluation and Research (CBER) to detect safety signals and to monitor drug safety.
During the December 11, 2002 hearing, Roche claimed that only 2,300 pregnancies had occurred among Accutane users since its introduction in 1982. However, Congressman Bart Stupak (D-MI), refuted that assertion, by citing a 1999 company report indicating that in a single 3 month period that year, 93 unwanted pregnancies were reported and 42 abortions occurred.
According to Dr Janet Woodcock, Director of the CDER at the hearing, AERS contained almost 23,000 adverse event reports for Accutane from the time of its approval in 1982 to December 2002.
For 2002 thus far, she said, AERS contains just over 1,100 adverse event reports. During 2002, she told the panel, the five most frequently reported reactions are, in descending order, depression, pregnancy, induced abortion, suicidal ideation, and headache.
Dr Woodcock explained that the Office of Drug Safety (ODS) within CDER maintains a quarterly cumulative count of reports of Accutane-exposed pregnancies and outcome, if known, based on Roche's quarterly submission.
The latest update as of June 2002, she said, "shows a total of 2,350 Accutane-exposed pregnancies and 172 babies born with a congenital defect or anomaly in the U.S. since the product was approved in 1982."
According to testimony by Dr Nancy Green, medical director of the March of Dimes Birth Defects Foundation, Associate Professor of Pediatrics and Cell Biology at the Albert Einstein College of Medicine, the major birth defects include a syndrome that includes mental retardation, hydrocephalus, microcephaly, cleft lip and palate, cardiovascular anomalies, and ear and limb abnormalities.
Lynn Martinez, Manager of the Organization of Teratology Information Services (OTIS), a national group that tracks prenatal birth defects exposure, informed the committee that OTIS was still receiving reports from women who had become pregnant while taking Accutane, despite the SMART program.
To measure compliance with the SMART program, researchers surveyed 34 women who had called a member service of the OTIS between April 2002 and September 2004 because they had become pregnant while taking isotretinoin.
The survey revealed that only 24% of the women received contraception counseling and while SMART required women to use two forms of birth control simultaneously while taking Accutane, only 62% of the women reported using any birth control and only 29% of those women reported using two forms.
According to the rules, women were required to have two negative pregnancy tests before receiving a prescription, but 76% said they did not have a second pregnancy test
When asked about the requirement of receiving a pregnancy test each month before refilling a prescription, 35% of the women surveyed said they did not have monthly pregnancy tests.
In addition, only 53% of the women reported signing the informed consent required by SMART prior to taking the drug.
Julia Robertson, coordinator of the Birth Defects and Genetics Program at the Utah Department of Health in Salt Lake City, and lead author of the study, said the failure to avoid pregnancy had resulted in a high rate of abortions and at least one baby born with severe birth defects.
The survey confirmed that the SMART program was not being followed by women or doctors, mainly because the program was not mandatory. The results of the study appeared online on October 14, 2005, in the journal Birth Defects Research (Part A): Clinical and Molecular Teratology.
The survey also revealed that the majority of women were prescribed Accutane off-label for less severe acne than is recommended by the SMART program.
At the December 11, 2002, hearing, the subcommittee discussed the problem of "off-label" prescribing to patients without severe cystic acne and some experts estimated it to be as high as 90% among women.
During the hearing, Roche's North American president and CEO, George Abercrombie, denied promoting Accutane for patients not suffering from severe acne. When confronted with print advertisements that featured teenage models with little or no visible acne, Mr Abercrombie pointed out that the ads did not specifically mention Accutane and said they were intended to make consumers aware that there were treatments for severe acne.
That statement went over like a lead balloon. "What you just said is not a truthful statement," Congressman Peter Deutsch (D-FL), told him. "You're beyond the straight-face test, I'm sorry."
Due to the failure of the SMART program, and the continuation of babies born with birth defects, in March 2006, the FDA implemented the iPledge program, which basically follows the same rules as the SMART program, but doctors and patients are no longer on the honor system.
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In addition, the woman must agree to use two forms of birth control while using the drug and she must also register with the iPledge system to certify that she is using two forms of contraception.
It could be said that Roche has between 300 and 450 good reasons to keep selling Accutane off-label to as many women as possible each month, because according to an August 21, 2006 article by the Associated Press, the daily pill costs between $10 to $15 a pop.