Randy Warren has no idea how people can balance on legs without the weight of their upper body falling over. The thought of a human walking bemuses him.

Warren, 38, has spent his life in a wheelchair, one of more than 10,000 people whose mothers took thalidomide to reduce morning sickness or insomnia during their first trimester of pregnancy. Half of the thalidomide victims, born between 1957 and 1962, are now dead. The survivors, some with seal-like flippers in lieu of feet or hands, are a stark reminder of the harm that can come from not knowing enough about a drug's darker side.

Meanwhile, thalidomide is making a comeback as a treatment for cancer, leprosy and a number of other medical conditions. And Warren, chief executive officer of the Thalidomide Victims Association of Canada (TVAC), has made it part of his job to ensure that no babies born today or in the future are "ever, ever a member of our organization."

To that end, Warren has worked with the drug's maker, Celgene Corp., and the U.S. Food and Drug Administration (FDA) on an unprecedented packaging agreement whereby patients who receive a prescription of thalidomide will see a startling photo of a thalidomide victim every time they reach for a pill. The unidentified baby girl is smiling wide for the camera, her arms shaped like lobster claws, her feet like flippers.

Somewhere out there, she is now a grown woman who has lived her life in a wheelchair. Warren and the other thalidomiders, as they call themselves, have named her Melanie.

"She will be responsible for preventing a lot of tragedy," said Warren, whose mother took only two thalidomide pills during her pregnancy. "The message, the picture, says it loud and clear. We don't accept a world with thalidomide in it and we never will."

The story of thalidomide is the most notorious tragedy in the history of drug-making, with about 12,000 deformed babies and untold others lost during fetal development. Luckily, in the United States, drug regulators averted further catastrophe by stalling the drug's approval after an investigator at the FDA, Frances Kelsey, raised concerns about it in early 1961. The drug, already in use worldwide since 1957, was still being tested for approval in this country. A year into her job as one of seven medical officers hired to oversee drug development, Kelsey had noticed a report in a British medical journal about cases of peripheral neuropathy, nerve damage that causes pain and tingling in the extremities, in thalidomide users.

In November 1961, a German pediatrician announced that he believed thalidomide could be linked to an even more frightening side effect: a growing number of babies with horrific birth defects. By early 1962, Germany was pulling thalidomide off the market, and in the next few months, about 20 other countries followed suit.

Kelsey had prevented a tragedy in America, for which John F. Kennedy presented her with the President's Award in the summer of 1962. As a result of the thalidomide tragedy abroad, the FDA adopted stricter guidelines for testing medicines for use in humans to ensure that drugs such as thalidomide never make it through without strict oversight to expose dangerous side effects.

The Drug's Positive Effects

Despite the thousands of babies it crippled for life, thalidomide never really disappeared. Quietly, scientists were studying its positive effects. Not only was it a powerful sedative, but it also showed promise as an anti-inflammatory and had a strong influence on the immune system. Two years after it was pulled from most of the world market, an Israeli doctor, Jacob Sheskin, reported that thalidomide had helped to heal deep, intractable sores afflicting his leprosy patients. Word of the drug's success spread quickly throughout the world.

Gilla Kaplan, a researcher at Rockefeller University in New York, set out to explain how thalidomide prevented sores and skin eruptions in leprosy patients. Kaplan discovered that thalidomide reduced a cell-regulating substance called tumor necrosis factor. This gave it great promise for treatment of a number of immune diseases and cancer.

In 1998, 35 years after its dramatic effect on the sores of Sheskin's patients, thalidomide was approved by the FDA for leprosy.

Since it was introduced to the world in the 1950s, thalidomide has been marketed under 51 different names. Warren's organization, TVAC, is in touch with 15 American victims or their families, who obtained the drug from overseas. Seven American thalidomiders are still alive, he said. Throughout the world, mostly in emerging countries where drug regulations are lax, thalidomide is still being used by pregnant women, and handicapped babies are still being born.

In the early 1990s, thalidomide began to be used by AIDS patients through an underground market. Patients were buying thalidomide abroad for the treatment of Kaposi's sarcoma, a rare form of cancer. At the same time, doctors were requesting approval to use it for the experimental treatment of other conditions--from macular degeneration, a leading cause of blindness, to rheumatoid arthritis. Studies reported in the past two months have suggested that it can help control symptoms of myeloma, a cancer of the bone marrow, and Crohn's disease, a chronic inflammation of the intestines.

By 1995, when Warren watched a woman with macular degeneration swallow a thalidomide pill on a "60 Minutes" broadcast, he knew the drug was back. After the segment aired, he worked with others in his organization to create a position paper warning about the drug.

A year later, a CNN reporter called Warren about an FDA hearing that had been held on the new uses for thalidomide. Chairs set aside for thalidomide victims were empty during the meeting--yet neither Warren nor any member of his organization had been invited. "If you found us, why couldn't the FDA?" Warren told the reporter. That sound bite made it to the FDA, and within 24 hours there was an apology on behalf of the agency's thalidomide advisory committee.

The TVAC position paper got its first airing at a meeting of the Centers for Disease Control and Prevention in Atlanta. In a written statement submitted to CDC, the thalidomide victims demanded inclusion in the drug approval process. They wanted to ensure that the drug would always be called thalidomide. They wanted a skull and crossbones danger sign on every package. They wanted doctors to deliver the medicine one pill at a time.

"Who will explain to a thalidomide child in 2007 why they were born disabled because of thalidomide?" they wrote. "Who's going to take responsibility? Are you?"

As Warren and his disabled partners had hoped, their message was heard by Celgene representatives at the CDC meeting. In April 1996, company executives flew to Canada to meet with Warren and other TVAC members.

That's when Bruce Williams, Celgene's vice president for sales and marketing, brought up "the picture." The FDA had created a document to warn the new generation of patients about thalidomide's risks, and the agency had used a cartoon graphic, a simple line drawing, to show the drug's effects. Warren had already seen the graphic and was disturbed by its simplicity. He wished it were a photograph of a real child harmed by the drug.

Warren thought the Celgene executive looked uncomfortable when he broached the use of a photograph. But Warren, far from offended, was pleased. If he couldn't prevent the drug's use, he hoped at least to tell its story through a photograph. Ultimately, the FDA and Celgene agreed to use a photograph--along with a video and consent forms--as a key part of their effort to warn and protect potential users of thalidomide.

The FDA's decision to adopt an elaborate mandatory education program--called the System for Thalidomide Education and Prescribing Safety, or STEPS--was based on the agency's experience with Accutane, an acne drug introduced in 1982 with great fanfare. When Accutane's harmful effects on a developing fetus became apparent, its maker, Roche Pharmaceuticals, worked with the FDA to strengthen labeling and start a voluntary program to keep track of young women taking the drug.

The Accutane program hasn't worked, according to Cynthia Moore, who heads the birth defects and pediatric genetics branch at the CDC. "There are babies lost to Accutane and others being born with severe birth defects," Moore said. Even if children escape the brain swelling, heart problems or missing ears that the drug can cause, years later they can show severe developmental delays, she said.

"The problem with the pregnancy prevention program is that it is voluntary," Moore said. "We have no idea what is happening in those women who are not participating." Also, women can pass along medicine to a friend who has received no counseling on the dangers of becoming pregnant while using Accutane.

What's more, the educational materials Roche was delivering to women contained a line drawing of a baby with malformed ears and a head that looked a little out of proportion to the baby's body. "Somebody looking at this would not get the full idea of what we are talking about," Moore said.

The FDA was determined to leave no such doubt about the thalidomide message.

A Graphic Educational Campaign

Ronald Bash is an oncologist in New York who will go to great lengths to save his patients. Two years ago, one of his patients had a vascular tumor the size of a grapefruit on her face, and Bash dug into the underground market to find some thalidomide to treat her. Two weeks after she began taking the pills, the mass shrank.

Although she eventually died of the cancerous tumors, Bash believed that thalidomide bought her time. Recently, another troubling cancer case made him consider thalidomide again. His patient had exhausted all standard treatment.

With the STEPS program now in place, Celgene sent Bash a thick, glossy thalidomide education kit, including a consent form to be signed by both doctor and patient, detailed warnings about the risk of "severe, life-threatening human birth defects" and a four-page confidential questionnaire asking about the patient's sex life.

The STEPS kit also includes a short film in which a doctor discusses the risks to a developing fetus, stressing that any sexually active woman of childbearing age should be using two forms of birth control while taking the drug. The film ends with an appeal from Giselle Cole, the president of TVAC, urging, "Please be careful taking this drug . . . " The camera first zooms in on her face and then, as her message comes to an end, fades back to show her deformed body.

Bash's cancer patient read the documents, filled out the questionnaire and signed the consent form. Bash's signature was also required. The information would be sent back to the company, and the questionnaire forwarded to a physician at Boston University School of Public Health, who would analyze whether the patient was at risk for getting pregnant.

Women of childbearing age can't get the drug without a negative pregnancy test--and they must be retested every two to four weeks after use of the drug begins.

John Jackson, president and CEO of Celgene, said that the elaborate STEPS program is part of the FDA-mandated labeling, not just a recommended process. "Doctors must deliver this program, or their patients won't have access to the drug," he said.

When Bash's patient took his prescription to the pharmacist, he received a white, book-sized package with 14 capsules enclosed in blister packs. But when he opened the package to the sharply focused picture of the little girl with no limbs, he was shocked.

So was Bash. "I was horrified," the physician said. "My patient and I had already decided to use this drug, and he was well informed of the risks. But this . . . this was destructive. I can't believe the FDA would mandate putting a picture in with the prescription."

More than 8,000 Americans have received prescriptions for Thalomid, the brand name that Celgene agreed on after TVAC and the FDA said the name Synovir would not do. "They need to know this is thalidomide, and they shouldn't ever forget," TVAC's Warren said.

The precautionary material presented to patients is unprecedented, Celgene's Jackson said. "This is a huge step for the FDA, who . . . had prevented [thalidomide] from getting on the market in the 1950s. The past history of this drug has such an emotional charge that the FDA thought that there needed to be something different."

The thalidomide disaster was a sobering lesson for doctors who had long believed that the placenta protected the growing fetus from substances ingested by its mother. But what about the dozens of other drugs that are also known to cause birth defects?

"FDA's reaction has been to wait and see how well the thalidomide program goes," said Celgene's Williams. Some patients might be so put off by the campaign, he said, that they might avoid taking thalidomide even after it was prescribed.

Indeed, every time a patient reaches for a pill and removes it from the blister pack, the silhouette of a pregnant woman appears behind a red slash--and then the picture of the child Warren calls Melanie, staring at the patient, smiling.

Resources

For more information and a free brochure on thalidomide, contact the Thalidomide Victims Association of Canada, P.O. Box 9061, Sub. 40, London, Ont., Canada N6E1V0. Or e-mail: TVAC@home.com.

CAPTION: Randy Warren led the fight to have a photograph of a thalidomide victim, shown on opposite page, included with prescriptions of the drug.