Evelyn Pringle: FDA Needs To Ban Accutane
FDA Needs To Ban Accutane
By Evelyn Pringle
Unfortunately hundreds of parents already know that Accutane can cause some teenagers to commit suicide, but new evidence of a link between the acne drug and depression in the journal, Neuropsychopharmacology, will hopefully put an end to the years of claims by Hoffman-LaRoche that its drug is not responsible for the suicides.
Scientists from Bath University, with the University of Texas in Austin, reveal in the journal, Neuropsychopharmacology that experiments conducted on mice show that Accutane makes the rodents behave in ways recognized as depression.
Isotretinoin is a synthetic retinoid used as an oral treatment for severe nodular acne that has been linked with depression and suicide in patients. Isotretinoin is also sold under the brand names of Accutane, Roaccutane, Amnesteem, Claravis and Sotret.
The purpose of the Neuropsychopharmacology study was to test the theory that chronic administration of Accutane could lead to depression related behaviors in mice.
In the study, young male mice were given Accutane by daily injection for 6 weeks, which produced blood levels of the drug comparable to those reported in human patients taking Accutane.
"You can't ask a mouse if it is depressed," researcher Sarah Bailey, of the University of Bath, said. "So we used two tests to model behaviour."
Both tests involved putting the mice under stress. In one test, the mice were suspended by their tails and in the other, they were put in water and forced to swim. Under these circumstances, the study author's note, normal mice will swim, climb or thrash around in attempt to escape, in between periods of immobility when they appear to be resigned.
But a mouse that is depressed will spend a longer time in the immobile state than a normal mouse. In both the forced swim test and the tail suspension test, the researchers found that Accutane treated mice spent significantly more time immobile compared to mice who were not on the drug.
For years, Roche has denied that Accutane causes depression and suicide and internal FDA documents show the agency was aware of these risks almost since the drug came on the market.
In 1985, Accutane's package insert for physicians first mentioned reports of depression in patients being treated with Accutane. In 1986, the physicians were again notified that Accutane users who became depressed saw their depression go away when they discontinued the use of Accutane but that the depression came back if patients went back on the medication. Doctors were also informed that simply removing the patient from Accutane treatment may not be sufficient to treat the depression and that a follow up for depression may be necessary.
Jumping ahead to a decade later, a 1998 FDA memo states that: "Given all the pieces of evidence available, it is difficult to avoid the conclusion that Accutane can adversely affect the adult human brain in clinically significant ways and that Accutane use is associated with severe psychiatric disease in some patients."
The FDA memo recommends "active consideration of removal of Accutane from the market." The recommendation was ignored.
In April 1998, the FDA instructed Roche to strengthen the warnings on Accutane and alert doctors to the risks of "depression, psychosis and, rarely, suicidal ideation, suicide attempts and suicide."
But even then, Roche continued to mislead potential customers about the risks of suicide. Two weeks after the label change, on March 5, 1998, the FDA sent a warning letter to Roche telling the company to cease "false and misleading" advertisements which promote Accutane as an "effective treatment of severe acne... [that] minimizes negative psychosocial effects such as depression and poor self-image."
The FDA stated that, "This claim is particularly troublesome in light of information recently presented in a Dear Doctor letter that Accutane may cause depression, psychosis, and rarely, suicidal ideation, suicide attempts and suicide."
In conclusion, the FDA ordered Roche to "prominently disclose information about the psychiatric disorders described in the warnings section of the revised labeling" in Accutane ads.
Two years later, on September 18, 2000, the FDA's Dermatologic and Ophthalmic Drug Advisory Committee held a meeting to consider Accutane's risks of psychiatric disorders. By that time, the FDA had determined that from 1982 to May 2000, Accutane was associated with 147 suicides and hospitalizations for depression.
The Committee determined that further research was needed to establish Accutane's risks of depression, suicide and other psychiatric disorders, but failed to recommend that the FDA require such studies.
By 2002, the FDA had confirmed 173 cases of suicide among persons taking Accutane since its introduction in 1982. Because suicide figures are based on self-reporting, critics say, that figure is highly suspect. According to the FDA, only about 1% of the suicide adverse events are reported which means the actual figure could be as high as 20,000.
Reports of suicides in persons taking the drug have been reported in many other countries as well. According to the September 19, 2006, Guardian, the Medicines and Healthcare Products Regulatory Authority, in the UK has received 38 reports of people who have died, and 25 of the deaths were the result of suicide.
The World Health Organization has reports of 720 cases of psychiatric problems arising from the use of Accutane, including 84 suicides and suicide attempts.
The drug maker's explanation for the sudden unexpected suicides among teens on Accutane has always been to say that teens were likely to be depressed due to their acne.
"To date," Dr Baily, lead author in the mice study, points out, "the only evidence for any link with patients has come from individual case reports and such patient data is complicated by the psychosocial effects of having severe acne."
The new scientific evidence in her study will hopefully put to rest the ridiculous claim that teens on Accutane commit suicide because they have acne.
However, the news is not likely to offer much solace to all the grieving parents. According to the Guardian article, last year in the UK, Jason Spiller, 16, killed himself after starting the drug in April 2005. The previous year, David Roberts, a 20-year-old, killed himself, and in 1997, Seumas Todd, 20, son of the actor Richard Todd, killed himself while taking the drug.
The father of suicide victim, Liam Grant, 19, from Dublin, is suing Roche in an attempt to prove Accutane caused his son's death. According to the Guardian, Mr Grant has spent £340,000 on studies, including one published by the American Academy of Psychiatry, which scanned the brains of 15 people on Accutane, and 15 people on other acne medication. The study found changes in the part of the brain associated with depression.
The Guardian reports that Roche has offered Mr Grant a settlement of all his costs and the maximum compensation payable in the event of winning the lawsuit against Roche of around £800,000, but without any admission of liability, so Mr Grant has refused the offer.
Suicides by young people on Accutane in the US have continued. On January 15, 2006, 15-year-old Justin Zimmer, of Menasha Wisconsin, shot himself and his parents blame the Accutane he was taking.
For years, Roche has also denied that Accutane causes birth defects. But here again, FDA documents show the agency was aware that the company was suppressing information about the link between the Accutane and birth defects. For instance, in 1998, an 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."
As far back as 1990, an FDA memo reported that as a result of Accutane's risks of birth defects, "The magnitude of injury and death has been great and permanent, with 11,000 to 13,000 Accutane-related abortions and 900 to 1,100 Accutane-related birth defects."
The 16-year-old memo also states, "Accutane poses an imminent hazard to public health, and as such should be withdrawn immediately from the market."
Twelve years later, documents introduced at a December 11, 2002, Congressional hearing by the House Oversight and Investigation Subcommittee, revealed a 1998 letter to the FDA from an official at the CDC, that compares Accutane to the infamous cancer and leprosy drug Thalidomide, a well known cause of birth defects, stating, "we simply need to remove the drug from the market."
The Congressional hearing focused on Accutane's link to birth defects, depression, and suicides.
Roche claimed that only 2,300 pregnancies had occurred among Accutane users since its introduction to the market. However, Congressman Bart Stupak (D-MI), whose son committed suicide while on the drug, disputed that assertion, citing a 1999 Roche report indicating that in a single three month period that year, 93 unwanted pregnancies were reported and 42 abortions occurred.
The committee also discussed the unnecessary health problems caused by the high rate of "off-label" use of Accutane by individuals who did not have recalcitrant cystic acne, the only condition the drug is FDA approved to treat.
Dr Janet Woodcock, director of the FDA's Center for Drug Evaluation and Research, testified that, "A proportion of people treated with this drug in the last decade had mild acne and should've been treated with other drugs."
In fact at the time, the off-label use of Accutane was so prevalent, that some experts estimated that the improper use was close to 90% among women.
Of course Roche denied that the company was promoting Accutane for individuals not suffering from severe acne. When shown a number of print ads for Accutane that featured teenage models with little or no visible acne, George Abercrombie, Roche North American president and CEO, claimed that the ads did not mention Accutane specifically and were intended to make consumers aware that there were treatments for severe acne.
"What you just said is not a truthful statement," Congressman Peter Deutsch, (D-FL), said. "You're beyond the straight-face test, I'm sorry."
Currently under new FDA regulations, Accutane can only be prescribed to women who are enrolled in a federally regulated distribution program called iPLEDGE. To obtain the drug, women must comply with a number of requirements that include completing an informed consent form, and obtaining counseling about the risks associated with Accutane and birth defects and the requirements for the safe use of the drug.
The goal of iPLEDGE is to prevent any pregnancies in women taking Accutane. To that end, the program requires women to be on birth control for at least one month before taking the drug and to undergo 2 pregnancy tests before taking Accutane.
During treatment with the drug, women must take 2 approved forms of birth control simultaneously and have a pregnancy test each month.
Under the program, physicians must be registered with iPLEDGE and can only prescribe Accutane to patients who are registered and meet all the other requirements of iPLEDGE.
In addition, the drug can only be dispensed by a pharmacy registered with iPLEDGE, and pharmacies can only purchase Accutane from wholesalers who are registered with the program.
Last month, another serious side effect of the drug was reported in a study published in the August 2006, American Journal of Gastroenterology, that confirmed that people taking Accutane have an increased risk of developing inflammatory bowel disease (IBD).
IBD includes serious and extremely painful conditions like Crohn's disease and ulcerative colitis. Since Accutane, was approved in 1982, numerous cases have surfaced linking the drug to IBD, but no a systematic review of the association had ever been conducted until now.
Researcher, Dr Corey Siegel, from Dartmouth-Hitchcock Medical Center in New Hampshire, and colleagues reviewed all reports of Accutane associated IBD that were submitted to the FDA through the MedWatch system since the program began in 1996.
For the study, the researchers used a standard adverse drug reaction probability scale to gauge the likelihood that a particular IBD condition was caused by the use of Accutane.
The study determined that between 1997 and 2002, a total of 85 suspected Accutane related cases of IBD were reported. In four cases, Accutane was graded as the "highly probable" cause, by the researchers, while 58 cases were deemed a "probable" cause, and in 23 cases it was listed as a "possible" cause. None of the links between Accutane and IBD were graded in the category labeled "doubtful."
"Physicians and patients should be made aware of this possible association and it should be included in the already extensive consent process required before isotretinoin is prescribed," the researchers wrote in the journal.
Additional side effects associated with the drug were also revealed last month in a study that appeared in the August 21, 2006 Archives of Dermatology, conducted by researchers at the University of California, San Francisco, that found Accutane raises levels of cholesterol and triglyceride fats in the body.
The study reviewed the cases of 13,772 patients between the ages of 13 to 50, who were treated with Accutane between March 1995 and September 2002.
The results of the study showed that 31% of patients taking Accutane developed high cholesterol levels, 44% patients with previously normal levels developed high triglyceride levels, and 11% of the patients reported high liver transaminase (liver enzymes) levels.
To date, other serious side effects associated with Accutane include problems with the pancreas, liver, stomach, bones, muscles, hearing, vision, allergic reactions, blood sugar, or red and white blood cells. According to the iPLEDGE web site, the most common, less serious side effects include dry skin, chapped lips, dry eyes, and dry nose that may lead to nosebleeds.
The FDA needs to yank this drug off the market once and for all. Weighed against its endless list of serious side effects, there is no justifiable reason to keep it on the market. Let the drug companies develop a new drug to treat acne.
(Evelyn Pringle is
a columnist for OpEd News and an investigative journalist
focused on exposing corruption in government and corporate