Feared Thalidomide Showing Promise
Thalidomide: Just the name of the drug conjures up horrific images of children born with flippers instead of arms.
The drug was widely used in Canada, England and West Germany nearly four decades ago as a sedative and to combat nausea. But it was found to cause serious birth defects if ingested during pregnancy.
For that and other reasons, the drug was never licensed in the United States. But that may be about to change. In recent years, researchers have found what they believe are significant therapeutic uses for the drug, particularly against the complications of life-threatening ailments such as AIDS and cancer.
On Thursday and Friday, a Food and Drug Administration advisory panel plans to meet to talk about the problems and the promise of thalidomide.
“It is excruciatingly ironic that thalidomide--a drug that triggered a host of protections that govern drug research and regulation--should return,” said Art Caplan, director of the Center for Bioethics at the University of Pennsylvania. “Nonetheless, if there is a benefit associated with a drug, you shouldn’t hold its history against it.”
Researchers have found the drug useful against certain AIDS-related conditions, such as painful mouth ulcers, known as aphthous ulcers, and severe body wasting. Some AIDS researchers also are studying its effect on production of the human immunodeficiency virus in the body.
It also has shown promise in treating glaucoma, lupus and a chronic rejection state that can be deadly in bone marrow transplantation.
Furthermore, thalidomide has been used abroad for years in treating leprosy in Mexico, the Philippines, South America and Asia. Scientists believe the drug eventually also could have an effect on Crohn’s disease, multiple sclerosis, arthritis and even Alzheimer’s disease.
“There is definitely a renewed interest in this drug,” said Dr. Debra Birnkrant, a medical officer with the FDA’s division of antiviral drug products.
But can thalidomide ever escape its past?
Its proponents insist that it can, as long as the drug is strictly controlled to ensure it is not taken by pregnant women.
“A 25-year-old patient with AIDS does not remember the tragedy of what happened in 1960,” Birnkrant said.
Moreover, “if the data support that it’s a promising therapy, we clearly could not deny approval just because of its history,” she said.
Thalidomide first became available in 1958 overseas and was touted as a safe “miracle” drug because it induced a quick calm sleep without hangover-like side effects. It also appeared to relieve nausea in pregnant women.
But then, beginning in 1959 in West Germany and England, thousands of infants were born with gross deformities, most often shortened limbs that resembled flippers.
In 1961, before thalidomide was identified as the cause, its manufacturer sought approval for distribution in the U.S. But Dr. Frances Kelsey, a medical officer new to the FDA, wasn’t satisfied with the company’s data. She was concerned about the known side effect of nerve inflammation and also that the research indicated the drug acted differently in people than it did in animals.
Kelsey’s caution--and the revelations of the unfolding tragedy abroad--not only kept the drug out of the U.S., but also resulted in the strengthening of FDA authority in regulating new drugs.
“It’s definitely not a benign drug,” Birnkrant said. But she noted that the illnesses currently being treated with thalidomide in research are not benign, either. Under these circumstances, “the risk-benefit equation changes,” she said.
She and others stress that if the drug were approved, the labeling would have to contain strong wording reflecting its dangers, and probably would require a massive educational campaign, particularly against sharing the drug with others. “Thalidomide is not a drug for the general public,” Birnkrant said.
But even those actions might not be enough. For instance, even with education, some women taking the anti-acne drug Accutane have done so while pregnant, despite its history of causing birth defects. The cases of birth defects are rare, but they have occurred.
Moreover in Brazil, where thalidomide is used for leprosy, “there have been reports of thalidomide babies, and we’re all concerned about that,” Birnkrant said.
Thus, some have suggested that the drug be dispensed in small amounts and that pregnancy testing for women of reproductive age be required each time it is prescribed or refilled.
“I have no problem with that,” said Cynthia Pearson, executive director of the National Women’s Health Network. “I don’t think anyone’s privacy would be violated by such a requirement, considering the danger.”
Such conditions are not regarded as unusual. The FDA requires that patients who take Clozapine for manic depression undergo periodic blood tests to prevent a potentially life-threatening blood disorder that is a known side effect.
Thalidomide appears to work by suppressing the body’s natural production of a substance called tumor necrosis factor, a potent hormone that helps regulate the immune system and fights bacterial infections.
However, if the hormone is active for too long or at too high a level, it can cause serious medical problems, among them shock and body wasting.
In a study of AIDS patients with aphthous ulcers, which make it difficult to eat or swallow, 61% of those taking thalidomide experienced complete healing, compared with 5% taking a placebo. Ninety-one percent of those taking the drug had partial or complete healing, compared with 18% on placebo, according to Peter Andrulis, chief executive officer of Andrulis Pharmaceuticals of Beltsville, Md.
“Its effects have been striking,” Andrulis said.
His is one of two small companies competing to bring thalidomide to the U.S. market. The other is Cellgene of Warren, N.J.
Neither has submitted an application for approval, although this is expected soon.
When and if thalidomide is licensed, “we need to come up with a way to protect the unaffected population,” Birnkrant said. “The goal will be to get it only to the patients who need it.”
