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Giving Thalidomide a Second Chance

by Herbert Burkholz

In the early 1960s the very mention of the word "thalidomide" was enough to conjure up the vision of a parent's worst nightmare: the birth of a deformed child. During that period, approximately 8,000 babies were born in Europe with severe defects after their mothers had taken thalidomide. The drug, a sedative, had been virtually untested for its effects on pregnancy. In its reaction to the tragedy, Congress enacted legislation in 1962 that put into place the rigorous testing now required before a pharmaceutical product can be approved in this country.

Today, almost 40 years later, manufacturers are conducting clinical trials to see if thalidomide can treat inflammation common to a host of diseases, and combat weight loss and aphthous ulcers in AIDS patients. Other trials are studying thalidomide's effect on the eye disease macular degeneration; on breast, prostate and brain cancer; and on Kaposi's sarcoma (a form of cancer common in AIDS patients). If thalidomide is shown to be safe and effective for even one such use, it would represent a remarkable comeback for a drug that once was universally condemned.

The thalidomide story began when a marked increase in the number of infants born with a severe deformity of the limbs called phocomelia was noted in a number of European countries. The deformities eventually were linked to the use of thalidomide during pregnancy. Mothers who took the drug during the first trimester, when the limb buds of the fetus are formed, produced children with a wide but distinctive range of deformities. Some had no arms, just flippers extending from the shoulders; others had limbless trunks with toes extending from their hips; others were born with just a head and a torso; and still others had cardiac problems.

Thalidomide was manufactured by Chemie Grunenthal of Germany, and was sold over the counter and by prescription by many firms in many countries under license from the parent company. In the end, children in 46 countries were affected. The American company that applied to the Food and Drug Administration to market the drug under the brand name Kevodon was Richardson-Merrell.

Thalidomide was not a lifesaving drug, but only one of many tranquilizers that had come onto the market in the decade after World War II. It was promoted by its maker as being nontoxic, with no side effects, and completely safe for pregnant women. Not one of those statements was true. In addition to the teratogenic effect on the fetus, in adults it caused peripheral neuritis, a painful numbing of the hands and feet that is often irreversible, as a side effect.

There were scientific tests that, had they been conducted, might have shown thalidomide to be unsafe. The drug companies involved, however, did not perform those tests.

That thalidomide was never marketed in the United States was largely due to the stubborn skepticism of FDA's Frances Kelsey, M.D., Ph.D., whose doubts about the drug kept it out of American pharmacies. Assigned to review the thalidomide application, she fought a dogged defensive battle, blocking and parrying every attempt by Richardson-Merrell to gain approval until the news from the European countries made approval unthinkable.

Kelsey was particularly interested in fetal safety because during the 1940s she had worked on the antimalarial drug quinine and had noted that embryos lacked the ability to metabolize quinine. But she had other concerns. She wanted to know how the drug behaved in the human body. She wanted to know about its stability, about its effect on human metabolism, about its basic chemistry and pharmacology. How the drug worked in laboratory animals was not enough; she wanted to know how it worked in humans. Years later, she recalled that, "... at this time there was growing concern regarding the exposure of the fetus to drugs and other substances to which the mother was exposed during pregnancy. ... Furthermore, the harmful effects of German measles during pregnancy had been recognized ... . The recognition of peripheral neuritis developing particularly after long-term use of thalidomide raised in our mind the question as to what effect the drug might have on the fetus who might be exposed to it for up to nine months."

Kelsey wanted to know the answers to questions that often were not asked in those days. Neither Chemie Grunenthal nor Richardson-Merrell, the American licensee, could or would answer her questions, and so the drug went unapproved in the United States.

Long honored for her role in blocking the approval of the drug, Kelsey, who still works for FDA as deputy for medical and scientific affairs in the agency's Center for Drug Evaluation and Research, points out that thalidomide was the first drug application to which she was assigned after joining the agency in 1960. "They gave it to me because they thought it would be an easy one to start on," she now recalls. "As it turned out, it wasn't all that easy."

Although thalidomide was unapproved in the United States, it was never ignored by researchers. According to Debbie Birnkrant, M.D., of the agency's division of special pathogens and immunological drug products, "Research on the drug slowed somewhat after the tragedies of the late 1950s and 1960s, but it never really stopped."

One of the reasons for the continued interest centers on the compound Tumor Necrosis Factor (TNF) Alpha, a chemical mediator in the body. Serious infections such as tuberculosis, sepsis and cancer cause the level of TNF Alpha to rise. This elevated level may contribute to the detriment of a patient's condition. In cancer patients it may enhance the wasting process, while leprosy patients may deteriorate because of high levels of TNF Alpha. Thalidomide may have the ability to lower TNF Alpha levels. Results of some test tube and animal trials bear this out.

Another reason is the apparent ability of thalidomide to inhibit the growth of new blood vessels. This could prove useful in cases of macular degeneration, which results from an overgrowth of new blood vessels in the central portion of the retina where focus is controlled.

In the AIDS arena, thalidomide may have the ability to combat aphthous lesions in the mouth and esophagus. In AIDS patients, these ulcerous sores are large, deep and painful. They are also debilitating, and may lead to malnutrition because the patient cannot eat.

With so many diverse applications being tested, FDA originated a Thalidomide Working Group in 1994 to provide consistency among the agency's various review divisions with a particular emphasis on safety monitoring.

Thalidomide is not approved for use in the United States; however, in appropriate circumstances FDA allows restricted investigational use of the drug to treat the diseases now under clinical trials. Over the years, thalidomide has been given to hundreds of patients under FDA's program for single-patient investigational new drug applications (INDs). However, as Birnkrant points out, "We're now moving from a state of issuing compassionate INDs for thalidomide to a state where there are actual clinical trials going on."

Given the known serious toxicities of the drug, those people participating in the investigational programs are given strong and unambiguous warnings. Female patients are advised that taking even one thalidomide pill can cause birth defects. They are further warned:

Female patients are also reminded that no method of birth control is completely reliable except for abstinence, and that if the patient does not practice abstinence or has not had a hysterectomy, she must use birth control even if she believes that she cannot become pregnant. She must also refrain from any other activity, such as fertilization methods, that could result in pregnancy. She is also warned not to take the drug if she is nursing a baby.

A female patient must immediately stop taking thalidomide under the following circumstances:

A female patient is also required to have a blood or urine test for pregnancy on a monthly basis or more frequently if she has irregular menstrual periods. Pregnancy testing will also be done if the patient experiences vaginal bleeding, or if she misses a menstrual period.

Male patients must be willing to abstain from sexual intercourse or use a condom during intercourse while they are taking thalidomide and for at least one month after the last dose, because it is not known if the drug is present in semen.

In general, all patients are reminded that thalidomide has been prescribed for the individual only, and must not be shared with, or given to, others. In addition:

Any such side effects should be reported by the patient to his or her doctor, as well as additional side effects such as: mood changes, dry mouth, headache, nausea, constipation, increased appetite, puffiness of the face and limbs, dry skin, itching, low white blood cell count, thyroid problems, blood sugar that is too high or too low, and slow heartbeat.

Although there are risks involved in an investigational program with a teratogenic drug like thalidomide, Birnkrant points out that it is important to explain to the public and to the patients just how the drug should be used. "The goal is to minimize the risk, recognizing that it may never be zero."

Herbert Burkholz is a member of FDA's public affairs staff.

FDA Consumer magazine (September-October 1997)

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