By Michelle Meadows

Acne plagued Julie Harper throughout high school and college. She depended on makeup and wore her hair down over the side of her face. She gave up chocolate and french fries, only to find that neither made a difference. And she went through medicine after medicine, from over-the-counter creams to oral antibiotics.

These were not occasional pimples that vanish after a couple of days. This acne covered her face and left scars on her neck. "I had tried everything and felt frustrated all the time," says Harper, now a physician and assistant professor of dermatology at the University of Alabama-Birmingham--a career she chose due in large part to her struggle with acne.

Harper finally found a successful treatment nine years ago at the age of 22. She took a drug called isotretinoin (trade name Accutane) and watched her skin improve in just a couple of months. By the third month, her acne had disappeared. She says with clearer skin came more self-confidence and higher self-esteem.

Considered the biggest breakthrough in acne drug treatment over the last 20 years, Accutane is the only drug that has the potential to clear severe acne permanently after one course of treatment. (See "Why Acne Forms, and How Accutane Knocks It Out.") One course, which is typically five months, results in prolonged remission of acne in up to 85 percent of patients. A member of a class of drugs known as retinoids, Accutane is highly effective. But it doesn't work for everyone, and some patients need more than one course of treatment. Dr. Harper took a second course of Accutane one year after the first and has been free of severe acne ever since, now only occasionally using a topical medication.

No other acne medicine works as well for severe acne. Patients generally have to keep using other medications because they only suppress acne temporarily. But as powerful as Accutane can be in improving patients' lives, its adverse effects can be just as powerful. The drug is known to cause miscarriage and severe birth defects. Patients taking Accutane may develop potentially serious problems affecting a number of organs, including the liver, intestines, eyes, ears, and skeletal system. And some patients taking Accutane have developed serious psychiatric problems, including depression. More rarely, patients have developed suicidal behavior and killed themselves.

Because it is a high-risk drug, Accutane should be reserved for cases of "severe recalcitrant nodular acne," according to the product's labeling. This type of acne is resistant to standard acne treatment, including oral antibiotics, and is characterized by many nodules or cysts--inflammatory lesions filled with pus and lodged deep within the skin. These lesions can cause pain, permanent scarring, and negative psychological effects.

"Sometimes people tend to dismiss the impact of acne because it's not life-threatening, says Kathy O'Connell, MD, PhD, a medical reviewer for Accutane in FDA's division of dermatologic and dental drug products, Center for Drug Evaluation and Research (CDER). "But patients with severe acne know all too well the very real suffering caused by this disfiguring disease."

FDA approved Accutane in 1982, and since then, about 5 million people in the United States and 12 million worldwide have been treated with it, according to its manufacturer, Hoffmann-La Roche of Nutley, N.J. The number of patients taking the drug has increased, and half are females, most of whom are in their childbearing years (age 15-44). Because of concern about the drug's risks, FDA continues to evaluate Accutane and work with the manufacturer to maximize safe use of the drug.

Warning about Pregnancy Risks

When FDA approved Accutane, the drug was known to be teratogenic--able to cause birth defects. It was designated as Category X, meaning that it must be avoided under all circumstances during pregnancy. Nursing mothers also should not use Accutane.

Though not every fetus exposed to Accutane becomes deformed, the risk of birth defects among pregnant women is extremely high. These defects include hydrocephaly (enlargement of the fluid-filled spaces of the brain) and microcephaly (small head), heart defects, facial deformities such as cleft lip and missing ears, and mental retardation.

Reports in the literature suggest that about 25 to 35 percent of babies will suffer a malformation after exposure, and that doesn't account for other defects, such as learning disabilities, that aren't detectable at birth. Miscarriages and premature births have also been reported.

Though FDA approved labeling in 1982 that warned Accutane should not be used in pregnant women, reports of severe birth defects associated with the drug began to arrive in June 1983. Over the following years, a series of labeling changes and letters to pharmacists and prescribers of the drug stressed pregnancy warnings and sought to increase awareness about reported malformations.

Then, after an FDA review of pregnancy exposures to Accutane, Roche launched the Pregnancy Prevention Program (PPP) in late 1988 to further educate women using Accutane and their physicians about the dangers. The goal was to ensure that prescriptions would only be given to women with severe recalcitrant nodular acne who could comply with contraceptive requirements.

Roche sent PPP kits to physicians and encouraged them to review pregnancy prevention materials with patients before starting the drug. Materials included a contraceptive booklet, checklists to help assess whether patients could adhere to the drug's requirements, and consent forms that patients sign to acknowledge their understanding of the risk of birth defects. Roche also set up a toll-free line, made contraceptive information available in 13 languages, and offered to pay for contraceptive counseling and pregnancy testing by a specialist.

To further reinforce pregnancy prevention, Roche began packaging Accutane in blister packs that include red and black warnings, along with a drawing of a malformed baby and the "Avoid Pregnancy" symbol.

Even though Accutane's labeling recommended use of two reliable forms of contraception, there have been reports of pregnancies occurring in patients who used hormonal contraception, including pills, injectables, and implantables, while taking Accutane. Accutane's labeling was updated in the summer of 2000. One change emphasized the need for two reliable forms of contraception for at least one month before taking Accutane, during treatment, and for one month after discontinuing Accutane, even when one of the forms of contraception is hormonal.

Evaluating Compliance

Yolonda Lawrence of Santa Monica, Calif., says there was no way she could miss the point about pregnancy prevention before she used Accutane for severe adult-onset acne in 1998. "I got a pamphlet, I signed papers, the doctor told me over and over, and the pictures of what can happen were very clear--babies with no ears" and other deformities, she says.

But reports of Accutane-exposed pregnancies continue, and that's enough to make FDA concerned, says Peter Honig, MD, director of FDA's office of postmarketing drug risk assessment (OPDRA) in CDER.

Shortly after the Pregnancy Prevention Program began, Roche sponsored a survey of women taking Accutane to assess compliance with the program, and the company encouraged doctors to enroll patients. Run by the Slone Epidemiology Unit at Boston University's School of Public Health, the survey set out to track pregnancy rates and outcomes, patients' awareness of risks, and patient and physician behavior.

Of the 500,000 women enrolled in the Slone survey from 1989 to 1998, there have been 958 pregnancies, 834 of which were terminations (either elective, spontaneous or due to ectopic pregnancies), 110 that resulted in live births, and 14 patients that had unknown outcomes. Of the 60 infants with available medical records, eight had congenital abnormalities. Since Accutane's approval, Roche has received close to 2,000 reports of Accutane-exposed pregnancies, 70 percent of which occurred after the PPP began.

According to FDA, exactly how well the PPP has worked is unclear. Experts say the PPP is a significant program that has prevented many pregnancies and is the first of its kind initiated by a pharmaceutical company. Roche has made extraordinary efforts to educate patients that they must not become pregnant while taking Accutane, says a Roche spokesperson.

At a September 2000 meeting of FDA's Dermatologic and Ophthalmic Drugs Advisory Committee, a Roche representative reported that from the company's perspective, pregnancy rates have declined. Amarilys Vega, MD, an FDA medical officer, agreed. However, because use of the product has increased over the years, the actual number of pregnancies occurring while taking Accutane has not declined. One limitation is that the survey is voluntary and only captures about 30 to 40 percent of all patients on Accutane. So there's no way to know exactly how many pregnancy exposures there have been, according to FDA experts. Of serious concern is that women who enroll in the survey may be more likely to comply with the contraceptive requirements than those who don't enroll in the survey. This leaves open critical questions about how representative the PPP group is and about unreported pregnancies among women who don't enroll in the PPP.

Most patients in the Slone survey have reported that they understood Accutane may cause birth defects. And according to Roche, the percentage of female patients who reported they were pregnant when they began Accutane dropped from 30 percent of pregnancies reported in 1989 to 11 percent of pregnancies reported for the period of 1991 to 1997. But substantial noncompliance with the PPP continues to be reported.

For example, a 1997 report on the survey shows that 25 percent of women in the program did not report having a pregnancy test before starting Accutane, and 33 percent did not report postponing the start of Accutane until a pregnancy test result was known. It is estimated that 40 percent of women taking Accutane are sexually active.

The only patients exempt from Accutane's contraceptive requirements are men, and women who have had a hysterectomy or who say they will abstain from sex during treatment. But the challenge is that going from sexually inactive to active can happen overnight.

Possible Psychiatric Link

Many patients say they feel better about themselves after receiving successful treatment for acne. Evelyn Germanakos, of Los Angeles, Calif., struggled with acne as an adult, and says she felt like her old self after Accutane cleared up lumpy blemishes in 1997. "I had gotten to the point where I didn't even want to go outside or be with people, let alone look in the mirror," she says. But while Accutane may help lift psychosocial distress such as embarrassment, evidence suggests that it may actually cause serious psychiatric disorders in some people.

Though the drug's label previously listed depression as a possible reaction, FDA strengthened the label warning in 1998 after reviewing cases with serious outcomes reported in the years after the drug was approved. The new labeling states that Accutane may cause depression and psychosis, and that in rare cases it may cause suicidal ideation (thoughts of suicide), suicide attempts, and suicide.

The label also advises providers that simply discontinuing the drug may not remedy any psychiatric problems and that further evaluation may be necessary. "In some cases, stopping Accutane alone may not be enough to relieve the mood changes," says Jonathan Wilkin, MD, director of CDER's division of dermatologic and dental drug products. "Psychiatric treatment may also be needed."

The relationship between Accutane and depression remains unproven, but some patients have reported that their depression subsided when they stopped the medication and came back when they resumed taking it. And some who have reported problems with depression while taking Accutane had no previous psychiatric history. FDA considers the number of reports of serious depression associated with Accutane high compared to other drugs in its database.

From 1982 to May 2000, FDA received reports of 37 U.S. Accutane patients who committed suicide, 24 while on the drug and 13 after stopping the drug. In addition to suicides, FDA received reports of 110 U.S. Accutane users hospitalized for depression, suicidal ideation, and suicide attempt during the same time period. As of May 2000, FDA had received reports of 284 Accutane users with non-hospitalized depression.

Several factors make it hard to definitively link depression with Accutane. Depression is a common problem, and some patients may be suffering from it before starting Accutane therapy. Additionally, some patients who reported depression with Accutane had previous courses of the drug without depression. Even so, it is recommended that doctors act as if Accutane could have psychiatric effects until there is more information, says FDA's Wilkin.

The Future of Accutane

Roche does not want to have any Accutane-exposed pregnancies, a company spokesperson says, and plans to continue educational efforts. This year Roche launched a targeted Pregnancy Prevention Program that focuses on women who are at highest risk of becoming pregnant while taking Accutane.

Experts agree that pregnancy prevention education should remain a key part of risk management for Accutane use. But more labeling changes and letters are not likely to make a significant difference, according to FDA's Honig. "During all the time the drug has been on the market and after all of those labeling changes, there are still pregnancies," he says. "It is not expected that another labeling change or 'Dear Doctor' letter will change behavior at this point." Psychiatric adverse events have also continued after labeling changes.

FDA's Dermatologic and Ophthalmic Drugs Advisory Committee met in September 2000 to discuss options for Accutane, and to evaluate whether a framework for safer use of the drug can be developed. One change since then is that all Accutane prescriptions now come with a new Medication Guide that contains warnings about pregnancy and psychiatric issues, plus other important warnings and precautions regarding potentially serious or life-threatening effects.

FDA has also proposed a mandatory registration of patients taking Accutane, prescribers, and pharmacists. "The main reason is to ensure that pregnancy testing is done before the drug is prescribed," says Julie Beitz, MD, of FDA's office of postmarketing drug risk assessment. The goal would be to have doctors document negative pregnancy tests and to have pharmacies dispense the drug only to women who have had negative pregnancy tests. The program to track Accutane patients is expected to be in place by summer 2001.

The registry for prescribers may involve a continuing education course that doctors would have to take to be able to prescribe Accutane. According to Hoffmann-La Roche, about 85 percent of Accutane prescriptions come from dermatologists and 15 percent come from primary care physicians. The course would be open to all medical doctors. And all Accutane patients would have to sign a mandatory consent form that would address both pregnancy and psychiatric issues, Beitz says.

The American Academy of Dermatology and the Dermatologic Nurses Association were among those who testified at the September 2000 committee meeting in opposition to a mandatory registration, saying that it would be a disservice to patients, making it harder for them to obtain the drug. Others, including the March of Dimes and the Public Citizen's Health Research Group, testified that they want to see stricter measures for Accutane.

FDA's experts say it's a balancing act. The value of Accutane is clear, but when it comes to even one report of death--whether it's suicide, miscarriage, or some other cause--FDA must make choices that will best protect the public's health.