Special Issue: Teen Health
Too Hard To Take
Tuesday, September 5, 2006
Virtually no one opposes the goal of the mandatory new federal program governing the use of Accutane: to prevent pregnant women from taking the potent acne drug, approved in 1982, because it causes serious birth defects.
That is where the consensus about the unusually restrictive six-month-old program known as iPledge ends. The program requires registration of all parties: wholesalers who sell it, pharmacists who dispense it, doctors who prescribe it and, above all, patients who take the drug.
Public health officials say such strict regulation is necessary because years of progressively stronger voluntary programs failed to prevent pregnancy in users of the medicine, a treatment of last resort for severe scarring acne. Most of the estimated 200,000 Americans who take the drug generically known as isotretinoin each year are under 30; half are female.
Others -- including Rep. Bart Stupak (D-Mich.), whose teenage son shot himself to death in 2000 while taking Accutane and who has addressed a congressional hearing on the drug's safety -- have long advocated tight controls, or a ban, on the drug because of its possible link to psychiatric problems.
But patients and their dermatologists complain that the rules of iPledge are onerous and unworkable and that the program is rife with problems that have disrupted and delayed treatment for thousands who have no other viable options.
Some doctors say they have spent hours on hold trying to reach the iPledge call center to straighten out problems with a patient's prescription. And some patients and their parents say they were given misinformation by program staff that prevented them from registering for the program, or encountered days of delay obtaining a password necessary to access its Web site.
Last week the 15,000-member American Academy of Dermatology (AAD) released a survey it commissioned bolstering those claims. The telephone poll conducted last month found that 90 percent of 378 physicians are having problems with the program, which is expected to cost the drug's four manufacturers at least $80 million for the initial phase. Nearly 52 percent said patients' treatments had been delayed because they were unable to pick up a prescription within seven days while 39 percent said their patients encountered technical problems using the Web site.
In June, after a torrent of complaints, eight senators led by Judd Gregg (R-N.H.) and Dick Durbin (D-Ill.) appealed to acting Food and Drug Administration (FDA) commissioner Andrew von Eschenbach to "address the procedural barriers plaguing the operation of the program."
"Every single one of my patients has had a problem" said Washington dermatologist Sandra Read, a member of the AAD board. "I don't care how smart you are -- this is an extremely confusing program with a very steep learning curve."
Read said she has fielded calls from other dermatologists asking her to take over their patients because they had decided to stop prescribing the drug. Dermatologists estimate that Accutane costs about $600 per month and is usually covered by insurance.
Between 1982 and 2005, 2,796 pregnancies among women who used Accutane were reported to the FDA, according to Sandra Kweder, the agency's deputy director of new drugs. Most ended in abortion or miscarriage, but the birth of 194 babies with defects caused by the drug were reported to the FDA. The actual numbers are believed to be far higher, Kweder said, because pregnancies and birth defects among users are underreported.
Each year approximately 120,000 American babies are born with birth defects that result from genetic, environmental or, most often, unknown causes, federal officials say. The most common include cleft lip or palate (6,800) and Down syndrome (5,500), while tens of thousands of infants are born with signs of permanent damage caused by prenatal exposure to alcohol.
IPledge supporters acknowledge problems with the mechanics of the program, but say it serves an essential purpose.
"Acne is not a life-threatening disease," said Nancy Green, medical director of the March of Dimes, who called isotretinoin "a vanity drug" that has been over-prescribed for mild cases. Even though the program is, in her words, "cumbersome, laborious and flawed," she said it is critically important because of the drug's potential risks to a fetus.
Accutane and Amnesteem, Sotret and Claravis -- the trio of generics approved in the last four years -- are the only effective treatment for severe recalcitrant nodular acne, or cystic acne, the worst and most painful form of the skin condition, characterized by inflamed, pus-filled lumps that can approach the size of a quarter. In some cases, doctors prescribed the drug to patients with moderate acne that had not improved with other treatments. For about 80 percent of those who take it an average of five months, the results are remarkable. Their skin clears dramatically and often permanently.
"It has made a big difference in his self-esteem and he's got beautiful skin now," said Maureen Distad of Bowie of her 16-year-old son, who took the drug earlier this year. "I really didn't want him to take it," said Distad, who was worried about the widely publicized but unsubstantiated link to the risk of suicide in users, "but [his acne] had gotten to the point where the dermatologist said he was starting to scar and he said, 'I can't do this anymore.' "
Since the advent of the drug, dermatologists say, there have been substantially fewer cases of disfiguring acne, which can leave scars that are both physical and psychological.
"Anyone who says this drug is not lifesaving doesn't know what they're talking about," said pediatric dermatologist Robert Silverman, who practices in Fairfax and Washington. "I've treated at least half a dozen kids over the years who wouldn't leave their house because their acne was so bad, or who were suicidal because of how they looked."
Out of Patience
Dermatologist Susan Walker, director of the FDA's Division of Dermatology and Dental Products, says the program is working and that her agency is seeking to achieve "a critical balance of maintaining access to the drug and ensuring its safe use," in an effort to keep a "uniquely effective" drug on the market.
The FDA, she said, is "doing everything we can to maximize the efficiency of the program" by working with the sponsors. Walker declined to discuss possible modifications to iPledge.
Laurene Isip, a spokeswoman for Covance, the New Jersey drug development firm hired by the manufacturers to help design and administer the program, acknowledged in an e-mail that problems had occurred. But she said the situation has improved significantly.
Since March 1, when the program began, she said, approximately 165,000 patients, 25,000 physicians and more than 51,000 pharmacies have registered. "Overall we have made progress with the iPledge program," she wrote, adding that Covance has "worked diligently to rectify the situation by increasing telephone staffing and making the Web site more user friendly.
"It is important to note," she added, that the program is "unprecedented in size and scope."
Some dermatologists and patients say more fundamental changes are needed.
"Just this week I had two patients who were locked out of the system" because they failed to pick up prescriptions before the seven-day deadline, Silverman said. "One man just gave up."
Although Silverman said response time has improved, "I just don't have time to sit on the phone for five or 10 minutes, which still happens routinely." Silverman said he has no choice other than the call center: The Web site of iPledge is accessible only via an Internet Explorer browser that he cannot run on his office's Macintosh computer.
Holly Fenske said her 14-year-old daughter, Megan, was denied the drug for a month in the midst of treatment because the doctor made a clerical error on the girl's prescription.
"It was hell," said Fenske, who lives near Sacramento. The girl, who had spent four years battling one of the worst cases of acne her dermatologist said she had ever seen, told her mother "she was still ugly, still disfigured and felt like she wanted to die," recalled Fenske. "She felt she had just started to make some progress and it was being taken away from her."
Singling Out Accutane
FDA officials say the decision to implement what Kweder calls an "extraordinary" program in terms of its restrictiveness was made on the advice of an advisory committee in 2004, after a previous program called SMART failed to prevent an increase in pregnancies. Between April 2001 and March 2002, the year before SMART took effect, 150 pregnancies were reported to the FDA; during its first year, the number rose to 183.
In that two-year period, 325 Accutane users became pregnant, according to statistics compiled by the FDA; the outcome of 160 of those cases is known. Twenty-nine babies were born to Accutane users: 20 had no discernable problems, seven had birth defects consistent with the drug and the status of the other two infants was unknown.
Between Dec. 31, 2005, when enrollment for iPledge opened, and March 31, 2006, four weeks after the program became mandatory, no pregnancies were reported, said Walker, citing the most recent data available.
"That's good news for doctors and patients," she said.
Some doctors say they are concerned about reports that frustrated patients are buying the drug online from abroad or going to Canada or Mexico to obtain it, skirting all regulation. The FDA Web site explicitly warns against buying Accutane online.
And leading dermatologists ask why the agency hasn't imposed similar restrictions on other drugs known to cause birth defects. Among them are anti-seizure drugs approved for epilepsy that are now widely prescribed mostly off-label for depression and other psychiatric problems; the psoriasis drugs Soriatane and Tegison (which the FDA labels Category X -- never safe during pregnancy -- as it does Accutane); and over-the-counter vitamin A supplements, which in high doses can cause cleft palate, low IQ and heart defects, the same birth defects associated with isotretinoin.
"Putting isotretinoin but not all teratogens [drugs that cause birth defects] into a mandatory, restricted distribution program is arguably selective and discriminatory," wrote former AAD president Clay J. Cockerell and Diane Thiboutot, chairman of the AAD isotretinoin task force, in an article last month on Virtual Mentor, an online publication of the American Medical Association.
There's little doubt the drug responsible for the largest number of preventable birth defects is alcohol: An estimated 40,000 babies annually are born with symptoms of fetal alcohol exposure, which causes brain damage, facial deformities and mental retardation.
"We don't regulate alcohol," said the FDA's Kweder. She noted that Accutane causes birth defects at a rate approaching 30 percent -- far higher than epilepsy drugs and comparable to thalidomide, a drug once given to pregnant women to treat nausea. Thalidomide, banned in the United States in the 1960s, is now used to treat cancer under regulations similar to those for isotretinoin.
And that, said Green of the March of Dimes, is the purpose of regulation. Public health officials, she said, have a "social responsibility to protect against major high-risk outcomes. What's wrong with that?" ·