Thalidomide Back-Under Strict Control

Charles Marwick / JAMA v.278, n.14, 8oct97

THALIDOMIDE AND CONGENITAL ABNORMALITIES W. G. McBride / Letter to the Editor / The Lancet 16dec61 SIR,-Congenital abnormalities are present in approximately 1-5% of babies. In recent months I have observed that the incidence of multiple severe abnormalities in babies delivered of women who were given the drug thalidomide (` Distaval ') during pregnancy, as an antiemetic or as a sedative, to be almost 20%. These abnormalities are present in structures developed from mesenchyme-i.e., the bones and musculature of the gut. Bony development seems to be affected in a very striking manner, resulting in polydactyly, syndactyly, and failure of development of long bones (abnormally short femora and radii). Have any of your readers seen similar abnormalities in babies delivered of women who have taken this drug during pregnancy? Hurstville, New South Wales. W. G. McBride. *** In our issue of Dec. 2 we included a statement from the Distillers Company (Biochemicals) Ltd. referring to " reports from two overseas sources possibly associating thalidomide (` Distaval ') with harmful effects on the foetus in early pregnancy ". Pending further investigation, the company decided to withdraw from the market all its preparations containing thalidomide.-ED.L. Newborn male infant showing typically malformed limbs caused by thalidomide ingested by the mother during early pregnancy. (Moore, K. L.: Manit. Med. Rev. 43:306, 1963. )

THALIDOMIDE, the notoriously teratogenic agent of the 1960s, is about to become a prescribed drug. Just 17 days after an advisory committee of the Food and Drug Administration (FDA) recommended that the acting commissioner give marketing approval to thalidomide for treatment of erythema nodosum leprosum (ENL), a complication of lepromatous leprosy, FDA informed the maker that the drug would be approved.

This use has been studied since 1965. The condition is estimated to affect only a few thousand people in the United States, but when approval is granted, the door will be open for physicians to prescribe the drug as they wish. A number of uses of thalidomide are under active investigation and some have shown considerable promise. However, even apart from its teratogenic potential, the drug is not without such occasional serious adverse effects--especially with long-term use--as irreversible peripheral neuropathy.

Thalidomide is an inhibitor of the cytokine tumor necrosis factor (TNF-), a property that may make it useful in mediating such diseases characterized by an excess of TNF- as human immunodeficiency virus (HIV) infection and tuberculosis. Other conditions in which thalidomide has been clinically studied include Behçet disease, lupus erythematosus, chronic graft-vs-host disease, gliomas, Sj6gren syndrome, rheumatoid arthritis, and inflammatory bowel disease. The drug also seems to have antiangiogenic properties that have prompted interest in using it to treat some cancers and macular degeneration.

An investigator with Celgene Corporation, Warren, NJ, 1 of 4 US manufacturers of thalidomide, has said that he started to list the potential clinical uses and gave up when he got to 50. Overall, says the FDA, at least 1000 patients in this country are currently using thalidomide on a compassionate basis or in clinical trials. The agency has no figures but admits that there is probably also quite a bit of "under-the-counter" use.

In addition to its application for approval of thalidomide for treating ENL, Celgene is planning to apply also for marketing approval for the use of thalidomide to treat AIDS wasting syndrome, said Sol J. Barer, the company's president and chief executive officer. "We are also looking at its use in AIDS-associated chronic intractable diarrhea, graft-vs-host disease, and severe rheumatoid arthritis," said Barer in an interview, adding that the company has an ongoing program to develop and study the effectiveness of thalidomide analogs, compounds that retain its therapeutic benefits without the attendant toxic effects. In cell assay systems some of these compounds have shown potencies more than 10 000 times that of thalidomide, reported David Stirling, PhD, a research scientist at Celgene, at a recent meeting. He said he expected that some of these compounds would be ready to enter initial clinical trials later this year.

Federal Agency Workshop

Stirling spoke at a workshop held last month at the National Institutes of Health (NIH) by that agency, the FDA, and the Centers for Disease Control and Prevention (CDC). The workshop was prompted by concern about burgeoning interest in the drug as a therapeutic agent and concomitant concern about thalidomide's teratogenic properties. At the meeting, federal officials, pharmaceutical firm representatives, physicians, and interested others-including persons with thalidomide-associated birth defects-reviewed and assessed the controversial drug. They discussed its clinical potential, risks to patients, ways to prevent birth defects associated with its use, and steps needed to monitor its safety and adverse effects. The meeting was held just days after the FDA advisory committee on dermatologic and ophthalmic drugs made its recommendation on the use of thalidomide to treat ENL.

The imminent availability of thalidomide and the increasing number of promising uses for it have raised concern that its inadvertent use by pregnant women could lead to a repetition of the situation in the 1960s when approximately 10 000 limb-reduction defects and other fetal abnormalities occurred worldwide (see sidebar). Despite the belief that there is considerable clandestine use of thalidomide, none of the fetal abnormalities associated with it have been reported recently, said Cynthia A. Moore, MD, acting deputy chief of the Birth Defects and Genetic Diseases Branch of the CDC.

No one at the workshop suggested banning the drug outright because of its teratogenic potential. Rather, the concern was that its use be adequately controlled and distribution carefully monitored, that some system of postmarketing surveillance be put in place, and that the medical profession and the public be adequately educated regarding the drug.

There is some evidence from a preliminary survey by the FDA on over-the-counter drug labels that those least aware of the teratogenic effects of thalidomide are those most at risk: persons under the age of 45 years. "We asked people to define a series of words just as if they had seen them in a dictionary, and one of them was thalidomide," said Louis A. Morris, PhD, chief of the FDA's Marketing Practices and Communications Branch. "We found that two thirds of those under 45 years didn't recognize the word, while those over 45 years of age at least recognized the word even if they didn't get all the details about thalidomide correct. Thalidomide rang a bell with them." Morris noted that the survey involved only 130 people, a very small sample, so, he said, "you don't want to make too much out of it. But the results are striking."

One way to prevent the occurrence of birth defects associated with thalidomide is to limit it strictly to proven uses and to patients who cannot become pregnant. This, however, would mean that much of the use of the drug would be in uncontrolled circumstances, said Janet Woodcock, MD, director of the FDA's Center for Drug Evaluation and Research.

This point was picked up by Randolph Warren, chief executive officer of Thalidomide Victims Association of Canada, London, Ontario. A thalidomide victim himself, he expressed revulsion at the prospect of the drug's reappearance. "We will never accept a world with thalidomide in it," he said; "however, we are forced to adopt a position of preferring regulated thalidomide over unrestricted access." Warren also said he believes that when thalidomide is approved, some birth defects will inevitably follow.

He was not alone. Discussing ethical issues associated with the use of thalidomide by fertile women, Norman Fost, MD, director of the Program in Medical Ethics at University Hospital, Madison, Wis, warned, "There is no system that will prevent the single birth of a child with phocomelia. The problem is to find some middle ground that properly balances the interests of future children and getting reasonable access to the drug."

Ethics Over Exclusion

Noting that thalidomide has the potential to be an effective agent for a number of conditions, Gail J. Povar, AID, clinical professor of medicine and health care science at George Washington University School of Medicine, Washington, DC, addressed the problem of off-label use-an issue that cropped up repeatedly during the workshop discussions. The data presented at the meeting provide a strong incentive to approve and promote the use of the drug. Povar noted, adding, "What worries me is that there may be desperate patients who will try to go beyond the well-documented indication. to more experimental applications. When you do so, the ethical requirements go up. They extend beyond the informed consent and risk-benefit assessments of standard medical practice to those of clinical research."

Few drugs carry the pharmacologic political and emotional baggage that is attached to thalidomide, Povar said. Therefore, some maintain that the drug should be excluded from use by fertile women. that its teratogenic effects pose an ethical issue that makes it different from other drugs. This attitude, she said, is a mistake. "Thalidomide poses no more and no less of a challenge than any drug with substantial promise and toxicity. We are simply dealing with an agent that. like any pharmacologic agent, purchases its effects at a price. There are benefits, but there are also risks, and physicians must weigh them carefully."

In the expectation of marketing thalidomide. Celgene has drafted a plan that it hope. will prevent fetal exposure to the drug. "The goal is zero defects," said Bruce A. Williams, the firm's vice president for sales and marketing. The plan is built on experience with restrictions on such other drugs with severe adverse effects as Accutane (Hoffmann-La Roche, Nutley. NJ), used to treat severe acne, and Clozaril (Novartis Pharmaceuticals

Corporation, East Hanover, NJ), used to treat schizophrenia. However, the plan has some unique elements, Williams said. The manufacturer -%-.ill exert "a high degree of control" over distribution of the drug and, unlike the system used by Hoffmann LaRoche to control the use of Accutane, a tracking system would be in place to ensure compliance.

The plan has yet to be finalized, but Williams said he believes it goes a long way toward solving the problem. "It's a model for the distribution of drugs that have great benefit yet significant frisk. It is a response to both the need to prevent a new thalidomide tragedy and the humane need to ensure that those who need this therapy can have appropriate access to it," he said.

Essentials of the Plan

The goal is to limit risk by supporting appropriate use for serious, debilitating, life-threatening conditions for which current therapy is inadequate or unavailable. Williams described a scenario in which a patient, considering the use of thalidomide and in consultation with a physician, would agree to counseling regarding the relative risks and benefits to ensure that the risks, including the need to avoid fetal exposure, were understood. The patient would sign an informed consent document that acknowledged his or her understanding and would agree to participate in a confidential survey at the start, during, and on the completion of therapy. Patients would be warned against letting the drug be used by anyone for whom it had not been not prescribed.

Women would be counseled about contraception; the results of a pregnancy test would have to be in hand before therapy was started; and pregnancy tests would continue during the course of therapy. "This is not a contraceptive program, it's a fetal risk-exposure prevention program," Williams emphasized. A prescription would be written for only 4 weeks of therapy, and no automatic refills would be allowed.

Male patients who are prescribed the drug would be advised to use condoms if they are sexually active. "The authorities we've talked to strongly urge us to recommend the use of condoms, in part because it's good policy from the public health perspective and in part because we can't categorically rule out the risk of the drug being transmitted in the ejaculate, although when it's been looked for it has not been found;" said Celgene's Barer.

One unusual recommendation the advisory committee made was that warnings on the package include a photograph of a limb-deficient infant as a dramatic illustration of the potential consequences of misuse.

Only physicians and pharmacies that comply with the program will be able to prescribe and dispense the drug. Pharmacies filling prescriptions for thalidomide must agree to participate in a patient-tracking system that registers all patients. The information will be confidential, and women patients will be surveyed once a month, men every 3 months. The registry will enable tracking compliance with the program; the data will be independently evaluated by the Slone Epidemiology Unit at Boston University School of Medicine, which has long experience evaluating prescription drug use. "This will provide us with constant feedback on how the program is working and how we can learn from it," said Williams.--by Charles Marwick