FDA vs Accutane

FDA Consumer: New warning about acutane and birth defects - includes related article: "New Warning About Accutane and Birth Defects

The issue before FDA was whether a drug that has the ability to clear a very severe and disfiguring form of acne should be taken off the market because it also carries a high risk of causing a deformed baby or miscarriage if taken by a pregnant woman.

The name of the drug is Accutane (generically called isotretinoin). The issues surrounding it could serve as a basis for a course in medical ethics. Summarized, these issues are:

* A relative of vitamin A (see accompanying article), Accutane was known to cause birth defects in animals and suspected of causing them in humans even before it was approved by FDA in 1983. Although the labeling has always forbidden use of the drug during pregnancy, such use has nevertheless occurred. Marketing experience with the drug indicates that Accutane causes birth defects in about one out of every four exposed fetuses.

* The condition for which the drug was approved, severe recalcitrant cystic acne unresponsive to other therapy, is much more common in males than in females. Yet 40 percent of the prescriptions are written for women, virtually all of whom are of childbearing age. The primary reason given for this is that women seek treatment for thsi condition more often than men.

* Accutane is the only drug that can clear this severe and disfiguring form of acne. Other drugs approved to treat the same condition must be taken for extended periods and, when stopped, the condition usually reappears. But with Accutane, most patients need to take the drug for only a few months. When the drug is discontinued, the acne usually does not return.

* Birth defects continued to occur despite repeated revisions of the labeling, letters to physicians from the manufacturer, Hoffmann-La Roche, and articles in the FDA Drug Bulletin (a publication sent to more than 1 million health professionals) that the drug should not be used by women of childbearing age unless they were using an effective form of contraception. Miscarriages (technically called spontaneous abortions when occurring in the first three months of pregnancy) also continued to occur at a rate substantially higher than in the general population. In addition, there has been an increased rate of elective abortion among women taking Accutane, apparently resulting from the wish to avoid giving birth to a deformed child.

To publicly consider these issues, FDA convened a meeting last April of its Dermatologic Drugs Advisory Committee, a panel of experts from outside the agency. Highly knowledgeable and respected scientists lined up on both sides of the issue. Representatives from the federal Centers for Disease Control (part of the Public Health Service) and the American Academy of Pediatrics recommended that the drug be withdrawn from the market. Consumer advocates proposed severe restrictions. Spokespersons from the American Academy of Dermatology, representing skin specialists (who write 90 percent of all Accutane prescriptions), emphasized its therapeutic value and the physical and psychological scarring, along with the social ostracism, that patients with severe cystic acne often endure. They recommended continued marketing with a number of restrictions.

Proponents of keeping the drug on the market showed slides of patients with disfiguring acne, not only on the face but also on the shoulders, arms, back, and chest.

Proponents of severely restricting or totally banning the drug showed slides of babies with the birth defect syndrome known to be associated with the drug: mishapen head, lack of ears or ears placed low next to a too-small jaw, and cleft palate. They also described the defects of the brain and heart and explained that the drug does the most damage to the fetus in the early weeks of pregnancy, often before a woman realizes she is pregnant.

How was FDA to choose between protecting the unborn and healing patients with a disfiguring physical problem?

Should the agency allow a drug to remain on the market that continued to be a cause of birth defects despite warnings that it not be used in women who were pregnant or who might become pregnant?

On the other hand, could FDA ethically remove from the market a drug that had the capacity to clear up a disfiguring condition when no other marketed drug was as effective?

Fortunately, FDA had a solution available to it that was not available to Solomon: compromise.

Taking into account advice from consumer and professional organizations, the agency and Hofmann-La Roche have been hammering out further restrictions and unprecedented labeling warnings in the expectation that these will insure the appropriate use of the drug and, thus, the elimination of birth defects associated with its use.

One aspect of this plan is the inclusion, in the patient information labeling, of a drawing of a baby with the syndrome of deformities associated with Accutane use. The drawing is meant as an attention-getter and as a deterrent to women who might otherwise take lightly the warning not to take the drug unless they are using an effective form of contraception.

The patient labeling will also state that there is at least a one in four chance that a woman who becomes pregnant while taking Accutane will give birth to a deformed baby. The patient consent form, which the woman and her physician must sign, will include a discussion of the potential for birth defects. To prevent starting the drug when a pregnancy has begun but is not yet recognized, the patient leaflet will instruct the woman that the drug should be started only on the second or third day after the start of a normal menstrual period. A phone number will be given for women to call if they think they may be pregnant and want additional information.

The "don't use in pregnancy" symbol (a pregnant woman within a bisected circle, the international symbol for "not" or "don't") will be displayed both on each page of the patient leaflet and on each panel of the new blister-pack packaging. The blister pack will include a tear-off prepaid postcard addressed to Hoffmann-La Roche on which the patient can inform the company of her name, phone number, and address, and grant permission to the company to contact her for follow-up studies to determine whether women taking Accutane are continuing to become pregnant.

The physician labeling, which will also display the "don't use in pregnancy" symbol, will be extensively revised to more strongly emphasize the risk of birth defects. The print size for the boxed pregnancy contraindication will be doubled. The boxed warning will forbid Accutane's use in women of childbearing age unless all of the following conditions are met:

* The patient has severe, disfiguring cystic acne that does not respond to other therapies.

* She is reliable in understanding and carrying out instructions.

* She is capable of complying with mandatory contraceptive measures.

* She has received both verbal and written warnings of the hazards of pregnancy, the risks of contraceptive failure, and has acknowledged these in writing.

* Within two weeks before starting the drug, the patient has had a negative pregnancy test, performed in a physician's office or by a licensed laboratory.

The physician labeling will also contain instructions that Accutane should be prescribed only by physicians, such as dermatologists, who have special competence in the diagnosis and treatment of severe, recalcitrant cystic acne, and who understand the risk of birth defects.

In addition to the labeling changes, Hoffmann-La Roche has agreed to extensive professional educational and follow-up efforts. The firm will report to FDA all cases in which a woman using Accutane becomes pregnant, whether or not a birth defect or other adverse reaction occurs. It also will undertake research into the reasons why, despite warnings, pregnancies have occurred int he past. Data concerning the use of the drug, including information about age and sex of patients, will be supplied to FDA quarterly. The company is also designing studies using lower doses of the drug, and using higher doses for a shorter period.

This program is a bold example of what can be accomplished when a manufacturer, professional organizations, and FDA cooperate in finding ways to minimize the risks of a drug while preserving its availability to those who can greatly benefit from it. Only time will tell whether the responsible use of Accutane will make the decision to keep it on the market with increased warnings and restrictions a decision worthy of the wisdom of Solomon."

MY REACTION:

The lesson, as usual, is to use drugs responsibly.