Thalidomide Reemerges as Potential ‘Wonder Drug’
Imagine Jack the Ripper becoming prime minister, or the deadly Ebola virus turning into a boon to human health. Such a mind-boggling reversal of fortune is underway for one of the most horrifying medications of modern times: thalidomide.
The drug was notorious for causing thousands of birth defects and infant deaths in the 1950s and early ‘60s in Europe and Canada. Now it is being tested in labs around the world as a possible new treatment for many diseases, including leprosy, AIDS symptoms, and cancers of the breast, prostate and brain, as well as rheumatoid arthritis and complications of tuberculosis.
“It could be one of the wonder drugs of the 21st century, in terms of the range of diseases it might be effective against,” said Dr. Norman Fost, a pediatrician at the University of Wisconsin School of Medicine and director of the medical ethics program there.
The resurgence of thalidomide, which was originally marketed as a tranquilizer and sleeping aid, presents physicians, pharmacists and patients with numerous problems. The biggest, of course, is how to prevent another epidemic of birth defects. By the time the use of the drug was restricted in the early 1960s, 10,000 to 12,000 “thalidomide babies” had been born worldwide to women who took it during pregnancy. Half of the children died in infancy.
To its everlasting credit, the U.S. Food and Drug Administration did not approve thalidomide for general use here, largely because of unanswered questions about its toxicity. In 1962, Congress rewarded the agency’s caution by granting it greatly expanded powers to regulate drugs.
Now, in a move fraught with irony and danger, the agency that became a government powerhouse by keeping thalidomide out of the country is poised to approve it, perhaps in the coming weeks. Initially, the drug is expected to be recommended as a treatment for skin lesions associated with a type of leprosy. But once that door opens, researchers and agency officials say, there may be little to keep doctors from prescribing the drug for other ailments.
The FDA and the drug’s maker have planned extraordinary safeguards to prevent birth defects. Among other things, women of childbearing age will have to submit a negative pregnancy test before receiving the drug and agree to use at least two birth control methods.
Still, government health officials say tragedy appears inevitable. “If thalidomide is made available in the United States, it will be used by women of childbearing potential, and babies will be born with thalidomide” birth defects, Dr. Cynthia Moore of the Centers for Disease Control and Prevention told a government-sponsored scientific gathering last fall.
“It’s probably true, unfortunately,” FDA official Dr. Debra Birnkrant said of that grim prediction.
No one has struggled more vigorously with the challenges and dilemmas posed by the drug’s return than the president of the Thalidomide Victims Assn. of Canada. Randolph Warren, 36, said that he had malformed ears, malformed hips, “flipper-like feet” where his kneecaps should be, four fingers on each hand and “bones floating around my body.” His mother took only two thalidomide pills when she was pregnant, he said.
He has been working with the FDA and Celgene, a drug manufacturer, to create warning labels and packaging for thalidomide pills.
“It’s a moral quandary,” he said. “We believe that a thalidomide baby will be born, but how can we deny this drug to people who are suffering?”
‘A Big Difference in Patients’ Lives’
Although many countries restricted distribution of thalidomide decades ago, that did not stop scientists from studying the drug. Its comeback bid can be traced to a chance clinical observation in the mid-1960s: When doctors in Israel who gave the sedative to people with a type of leprosy, called erythema nodosum leprosum, the drug unexpectedly cleared up many of the skin lesions.
Since then, physicians have used thalidomide for that condition, said Dr. Stephen Rea, a leprosy expert at the USC School of Medicine. (U.S. physicians caring for leprosy patients had FDA permission to obtain the drug from overseas labs or other sources on a “compassionate use” basis.)
“It makes a big difference in patients’ lives,” he said of the drug. “People who were not able to work can go back to work.”
In 1996, Celgene, which sponsored recent studies on thalidomide, applied for FDA approval to sell the drug for treatment of leprosy. In October, the agency sent the company an “approvable letter,” indicating that the application was likely to go through.
If the drug were exclusively for the estimated 5,000 people in the United States with leprosy, there would be little concern from government--and little interest from the industry. But even Celgene acknowledges that it is setting its sights on other applications, such as AIDS and possibly cancer.
“Our interest is clearly not [just] in leprosy,” said the company’s vice president of sales and marketing, Bruce Williams. Regarding the danger of birth defects, he said: “Our objective is to develop and manage a [distribution] system with the goal of no failures.”
Traditionally, the FDA has not kept physicians from prescribing drugs explicitly approved for one disease to treat another, unspecified ailment--a practice known as “off-label” use.
The agency has sent mixed signals over whether--once it grants approval for use against leprosy--it will permit off-label prescribing of thalidomide or invoke seldom-used regulatory power to prohibit it. Still, Birnkrant, head of the FDA’s 4-year-old thalidomide working group, emphasized in an interview that doctors are ultimately responsible for prescribing the drug safely.
“It’s really something between a physician and his or her patient,” she said. Also, she said physicians who prescribe a drug for off-label purposes are especially vulnerable to malpractice claims if things go wrong.
But some experts oppose letting physicians prescribe the drug at will. “I think there should be a prohibition of off-label use,” said Fost, of Wisconsin. He added that thalidomide should be regulated as a “controlled substance,” like morphine, which can be prescribed only under narrowly defined circumstances and is closely monitored by state and federal authorities.
“No drug comes close to [thalidomide] in terms of the risk to future children,” Fost said.
Dr. Jeffrey Fessel, director of the HIV research unit at Kaiser Permanente Medical Center in San Francisco, recently told the trade publication Physician’s Weekly that women capable of having children should not be allowed to take thalidomide “under any circumstance.”
The only women given thalidomide in Kaiser’s HIV research program have already gone through menopause or had hysterectomies, he said. “If a child is harmed by thalidomide,” Fessel said, “I don’t want to have been the agent of that action.”
But legal experts and medical ethics specialists say government action to limit the drug to men and only those women who cannot have children would go against the Constitution’s guarantee of equal protection.
Controversy Over Use by Women
One of the few people who has argued publicly against FDA approval of the drug for any use is Thomas Bleakley, an attorney in Detroit and an expert on birth defects litigation. In the 1960s, he represented six of the seven children known to have been born in the United States with disabilities related to thalidomide, which had been distributed to numerous doctors, and used by some women, in anticipation of FDA approval.
Bleakley said that not all women would adhere to the strict birth control regimen mandated by the FDA and drug manufacturers. Thalidomide shows promise as a treatment for at least two complications of AIDS, and he expressed doubt that heroin-addicted women who acquired the infection by sharing intravenous needles would be able to follow the guidelines.
“The thought of giving them thalidomide sends chills down my spine,” he said. “The potential risk to our society is so great that we ought to look elsewhere” for treatments.
The FDA’s Birnkrant dismisses that scenario as unfair to women. “Just because someone is an IV drug abuser doesn’t mean they can’t take this drug responsibly,” she said.
Despite the drug’s risks, it has fervent advocates. Some argue that many prescription drugs--especially the highly toxic ones used in cancer chemotherapy--are known to be capable of causing serious birth defects, but that does not deprive female patients of the benefits.
“The question is how to use it appropriately,” said Dr. Howard Fine, chief of neurooncology at the Dana Farber Cancer Institute in Boston. “Keeping thalidomide off the market because of an inappropriate use in the past doesn’t help people hurt in the past, but it could hurt people in the future who might benefit from it.”
One widely used drug that is well known to cause severe birth defects is the acne medication Accutane. It comes in a tightly sealed packet that prominently warns women of childbearing potential of the risks. They are strongly advised to undergo a pregnancy test before being treated with the oral medication.
Curiously, both sides of the thalidomide debate cite the Accutane precedent: Advocates view its packaging and controlled distribution as something of a model, while opponents say recent experience highlights the pitfalls of such a medication.
Public health authorities estimate that three out of every 1,000 women become pregnant while on the medication. A third of those pregnancies result in children with severe birth defects, Fessel said.
Bleakley said that he knew of 34 babies born with deformities linked to Accutane in the past four years.
As for thalidomide, Fost said American society should try to reach a “social consensus” on the number of birth defects that would be acceptable, given the drug’s benefits.
The March of Dimes has already drawn the line, according to medical director Dr. Richard Johnston Jr.: “If one pregnant woman receives thalidomide,” he said in a statement, “that should trigger a reevaluation of the conditions of release of this drug.”
Drug May Affect Bodily Processes
Scientists say they have barely scratched the surface of how thalidomide works in the body. But the fact that it seems useful against numerous diseases suggests that the drug affects many bodily processes.
For one thing, thalidomide appears to suppress a substance secreted by immune system cells known as tumor necrosis factor, produced in response to cancers and infections. Because an excess of tumor necrosis factor may contribute to body wasting in cancer and AIDS patients as well as inflammation that accompanies a number of diseases, medical researchers are studying whether thalidomide may improve healing in such conditions.
Another reason that the drug holds promise against some cancers, researchers say, is that it curbs the growth of new blood vessels, which tumors require to keep flourishing. This approach to cancer therapy, known as anti-angiogensis, is one of the hottest areas of cancer research today.
The only completed study of thalidomide and cancer was led by Fine in Boston. Beginning in 1996, the cancer researchers tested thalidomide in 39 patients with severe brain tumors who had run out of treatment options.
In his study, Fine found that thalidomide seemed to halt or slow the growth of brain tumors in many patients, but that the benefit was not permanent. Clearly, he said, thalidomide was no cure, but if further studies validate his findings, he could foresee it becoming another tool that oncologists use against the disease.
Thalidomide has also shown promise against at least three complications of AIDS. In one of the most dramatic studies so far, researchers based at the National Institutes of Health tested the drug on AIDS patients with painful mouth and throat sores known as apthous ulcers. The drug cleared up the sores in 16 of 29 patients studied, whereas only two of 28 patients taking a placebo saw improvement.
Several preliminary studies also suggest that the drug fights the devastating weight loss frequently brought on by AIDS, helping some patients put pounds on within weeks. Dr. Morris Shambelan, an AIDS researcher at UC San Francisco who is testing the drug on patients, said thalidomide has some advantages over other drugs used to treat AIDS wasting. For instance, it’s much less expensive than human growth hormone, a genetically engineered drug, he said.
Indeed, thalidomide’s effects on complications of AIDS, including the cancerous lesion called Kaposi’s sarcoma, led to formation of underground “buyers clubs” that obtained the drug from Brazil or other countries where it has remained legal.
Though the FDA was aware of those underground suppliers, it allowed them to function, sources say, because the drug showed promise and no legitimate outlet was available in the United States.
But as it became clear that Celgene and other drug companies were gearing up to produce thalidomide under the stringent manufacturing conditions mandated by the FDA, the agency moved to shut down the black market last year.
“Having a reliable product out there . . . would discourage underground use of this drug,” Birnkrant said.
Warren of the victims group said the existence of the buyers clubs “practically forced us to prefer regulation of the drug. Logically, we had no choice.”
