In early September, an advisory committee to the U.S. Food and Drug Administration (FDA) recommended that the FDA approve marketing of thalidomide for erythema nodosum leprosum, an inflammatory manifestation of leprosy that results in painful cutaneous lesions on the arms, legs, and face. The committee also strongly recommended limiting distribution of thalidomide, with stringent safety measures put in place to avoid birth defects and other side effects.

The renewed interest in thalidomide comes from studies showing a complete response in 90% of patients with erythema nodosum leprosum who used thalidomide, according to Janet Woodcock, MD, chief of the FDA's Center for Drug Evaluation and Research. The drug is also under investigation to determine its effectiveness against graft-versus-host disease, the AIDS wasting syndrome, some solid tumors, certain serious primary dermatologic conditions, tuberculosis, aphthous ulcers, and macular degeneration. Woodcock said that evidence is most compelling for the drug's effect on aphthous ulcers in patients with HIV infection (N Engl J Med. 1997; 335:1487-93) and with Behcet disease. She considers the data on the AIDS wasting syndrome "promising" but preliminary.

The committee's recommendation was preceded by a year of intensive debate and planning because of the drug's potentially severe side effects. Even one dose of thalidomide, when taken during the early stages of pregnancy, can cause fetal deformities. The drug can also cause peripheral neuropathy, sometimes resulting in permanent nerve damage.

A Brief History

Thalidomide was originally marketed as a sedative and was often used for morning sickness outside of the United States in the 1950s and early 1960s. Although thalidomide was the third largest-selling drug in Europe-considered so safe it was sold over-the-counter in many places-it never passed FDA scrutiny. At least 8000 of the babies born to women who took the drug during pregnancy had phocomelia, which is characterized by missing digits, arms and legs, and internal organ deformities. In the United States, 17 babies were born with the rare birth defect; their mothers had received the drug from overseas sources or received premarketing samples distributed by drug company representatives. The thalidomide episode resulted in stricter review requirements for drug approval by the FDA, including proof of safety and efficacy plus informed consent by all participants in clinical trials.

Today, the FDA has in hand new data that indicate thalidomide's promise in fighting several serious diseases for which no effective alternate therapy exists, but the risks, of course, remain. Because many of the diseases in which thalidomide is potentially beneficial afflict young women (Behcet disease, the Sjogren syndrome, Crohn disease, and rheumatoid arthritis), issues of teratogenicity are critical. Because of a recent study showing thalidomide in rabbit semen and uncertainty about its presence in human semen, both women and men receiving the drug will be required to use contraception.

Concerns about birth defects have been so great that investigational use of thalidomide for erythema nodosum leprosum has been limited to men and postmenopausal or surgically sterilized women. The FDA is unlikely to limit general use of the drug to that extent, but if it is approved as proposed, thalidomide will be the most restricted drug in the United States, Woodcock confirmed. Every physician, pharmacist, and patient involved with thalidomide will be required to adhere to a tightly controlled protocol, according to Bruce J. Williams, from Celgene Corporation of Warren, New Jersey, the drug's marketer.

To gain access to the drug, patients will be required to receive risk–benefit counseling, sign an informed-consent agreement, use two forms of birth control, and participate in frequent surveys; monthly prescriptions will only be filled after pregnancy testing. Compliance and fetal exposures will be tracked. Only pharmacists registered to participate will be permitted to dispense the drug. By registering, they commit to dispense thalidomide in 28-day supplies in original packaging (special blister-packs with pregnancy warnings encasing each pill) only after seeing the signed informed-consent document. The drug cannot be dispensed as a simple refill, and patients will be advised to return unused doses.

When asked whether a patient using thalidomide can decline the use of birth control for religious or other reasons, Williams responded: "Women can make informed choices about whether or not to take the drug. But if they are of childbearing age and want the drug, they must use contraception." Boston University researchers will maintain a thalidomide users registry modeled after the registry that tracks use and pregnancy outcomes for users of isotretinoin, which is marketed by Hoffman-La Roche in Nutley, New Jersey, under the trade name Accutane (Box).

Zero Risk Impossible

Even with these unprecedented safety measures, experts admit that zero risk is an impossible goal. Babies will be born with birth defects if thalidomide is made available. But based on the isotretinoin experience, 20 years of testing in erythema nodosum leprosum, and limited use of thalidomide by 72 women with the AIDS wasting syndrome or aphthous ulcers, the FDA is prepared to move ahead.

Implications of this regulatory action go beyond U.S. borders. It sends a message to other countries, said Colin Crawford, MB, ChB, DPH&H, from London's Imperial College of Science, Technology, and Medicine. If the U.S. government makes thalidomide available, developing countries may do the same, he predicted, most likely without the comprehensive safety and tracking program being planned for the United States.

Thalidomide is already available in 8 of 10 South American countries. Thirty-four cases of thalidomide embryopathy have been reported since 1965. Most have occurred in Brazil, where the prevalence of leprosy is high and where, until recently, thalidomide was available without a prescription.

In the United States, the communications challenges are twofold. A population of patients vividly remembers the first thalidomide tragedy. But an informal FDA poll found that most people under age 35 have never heard of thalidomide and are unaware of its potential harmful effects. "When communicating about risks of any disease to a patient, we have to be aware of the cohort experience that patient brings," said Gail J. Povar, MD, clinical professor of medicine and health care sciences at George Washington University School of Medicine in Washington, D.C. Recalling her own reaction to the thalidomide news in the 1960s, Povar stated that nothing could have convinced her to take the drug if she had any chance of becoming pregnant. But she predicts that 25-year-olds will be furious if their physicians refuse to prescribe it for them. She has seen this happen with isotretinoin. "Every week I have a teenager ask for Accutane inappropriately. We have to accept the fact that this will happen with thalidomide and be prepared."

Advocates for survivors of thalidomide defects are calling for efforts to develop analogues of thalidomide without the harmful side effects. But analogue development may take some time because researchers are not sure exactly how thalidomide works. Its immunomodulatory effects may occur through selective inhibition of tumor necrosis factor, the inflammatory cytokine involved in many diseases. It may also block angiogenesis, the most likely reason for its reported effectiveness against some solid tumors and perhaps the method by which it blocks fetal limb and organ development.

"Thalidomide will likely spark dis-agreements both within the medical community and between medicine and the public about what limits, if any, to impose on use in fertile women. In addition, because of its exciting potential in the amelioration of serious illnesses, thalidomide may tempt clinicians to go beyond well-documented indications to more experimental applications," said Povar. "Informed consent becomes much more important here. Our obligation goes way up. We need to be very clear that use is experimental."

"For the most part, thalidomide poses no more-and no less-a challenge to the practitioner than any other drug with substantial promise and potential toxic effects," she continued. "It would be unfortunate if thalidomide was considered too risky because of its past. Physicians just need to work closely with patients."

-Cori Vanchieri