Banned in 1962, Thalidomide makes uneasy return

Drug is now being prescribed for treatment of blood cancers

By Mackenzie Carpenter
Pittsburgh Post-Gazette

PITTSBURGH (AP) — It was one of epic tragedies of the mid-20th century: babies born without arms and legs, sometimes deaf or blind, sometimes with brain or heart damage — all because their mothers were nauseated or sleepless during their pregnancies and given Thalidomide to ease their symptoms.

While the drug was banned in 1962, it is again being prescribed — this time for treatment for multiple myeloma and other blood cancers — which its victims, now entering old age, often destitute and in increasing pain, find difficult to accept.

“In my life of conscience and effort and survival, there is nothing redeeming about Thalidomide,” said Berrisford Boothe, a 52-year old Thalidomide survivor who is a professor in Lehigh University’s department of art architecture and design.

While he is only one of 26 named American victims, Booth isn’t alone in feeling that way. There are an estimated 6,000 Thalidomide survivors still living, mostly in Canada and Europe because it was never approved for use in the United States, although 20,000 women here were given the drug in clinical trials. There could, in fact, be many more Thalidomide victims in this country than previously believed because the drug’s birth defects were sometimes internal, not external.

When the German company that made Thalidomide formally apologized to victims last month after 50 years of silence, the response was anger, given the company’s resistance to increasing or broadening compensation to victims.

But for those suffering from multiple myeloma, or leprosy, the modern form of Thalidomide represents something akin to hope. For reasons not completely understood, the very same mechanism in Thalidomide that stopped healthy cell growth in fetuses also inhibits the growth of cancer tumors.

John Lister, a physician, vividly remembers a fellow student at Queens College in Canada who was a Thalidomide baby but never let her stunted limbs hold her back.

“I lived in student housing, and she was one of the girls who shared the house,” he said. “She was very independent, she’d learned how to get around — and she had a wicked sense of humor.”
For Lister, the memory has special resonance, because as division director for Hematology and Cellular Therapy at West Penn Allegheny Health System, he uses Thalidomide today to treat multiple myeloma and other blood cancers

In this country, the drug is trademarked as Thalomid by current manufacturer Celgene, a New Jersey-based biotech company, which has also been developing newer, more potent versions to treat these cancers, such as Revlimid, with fewer side effects.

While the drug, he said, is mostly used by people who are past childbearing age, strict controls — similar to those required for using the acne drug Accutane — are in place to ensure that women do not become pregnant while on the medication, including using two forms of contraception.

But Thalidomide remains controversial.

Writing in the Observer last month, legendary British newspaper editor Harold Evans said the German company — despite its apology — had still not acknowledged that it ignored evidence during the testing phase — and after it was released in 1957.

“A lie wrapped in an apology is still a lie,” Evans said.

Evans oversaw a massive Sunday Times investigation into the drug’s effects and lack of compensation for its victims in 1968, leading to a settlement by Chemie Grunenwald for German and British victims, but the company, he wrote, has resisted adjusting it for inflation.

“This is not a wonder drug. Aspirin is a wonder drug,” said Barry Gold, professor and chair of the department of pharmaceutical sciences at Pitt’s School of Pharmacy, who sponsored a forum several years ago titled “When Good Drugs Go Bad,” using Thalidomide as an example.

As a cancer treatment, “I don’t think it has a great deal of promise,” he added. “It doesn’t cure multiple myeloma and doesn’t always work in those suffering from the disease, and (it) can produce bad side effects, although there are a lot of drugs for the treatment of cancer you would never think of giving to a healthy person.”


Greater drug regulation

Thalidomide’s origins remain murky. For years it was thought to have been invented by the German manufacturer Chemie Grunenthal, which secured a patent in 1954, but Martin W. Johnson, director of the Thalidomide Trust in the United Kingdom, recently revealed evidence suggesting that Nazi scientists had tested it on humans as an antidote to nerve gases, such as sarin, in 1944.

If there is any silver lining to the Thalidomide scandal, it’s that it became a watershed for how drugs are regulated in this country. Despite severe pressure from pharmaceutical companies to market Thalidomide, Frances Kelsey, the first female head of the Food and Drug Administration, resisted and then refused permission after irrefutable evidence emerged of its links to horrific birth defects.
A doctor in Australia revealed that mothers who had taken the drug in the first trimester gave birth to children with all sorts of deformations, including phocomelia — absence of the arm with hands like flippers extending from the shoulders — as well as malformed and in some cases missing arms and legs.

In 1961 and 1962, the drug was withdrawn, Kelsey received the highest civilian award from President John F. Kennedy, and Congress enacted laws requiring a series of intensive safety tests on pregnant women before drug approval.

Thalidomide “is a poster child for how important it is to look carefully in animal models for its teratogenic effects (causing malformations of an embryo or fetus) and to accumulate a lot of data on the safety and toxicity of these molecules we’re putting into people,” said Gold.

Still, research for experimental use of Thalidomide continued, and in the mid-60s, it was found to clear lesions for those diagnosed with leprosy. By the late 1980s, Brazil and Mexico had approved it for use with their relatively large populations of leprosy patients — although CBS’s “60 Minutes” broadcast a report about a whole new generation of deformed Thalidomide babies growing up in Brazil.

In 1998, the FDA approved it for use as a therapy for lesions associated with leprosy but said it would establish tight controls on its use, including a patient registry and periodic pregnancy tests for women and other restrictions.


Other uses
The road to approval in this country began in 1991, when a Rockefeller University researcher found that the drug regulates a protein called tumor necrosis factor alpha, with possibly huge implications for AIDS patients. The researcher, Gilla Kaplan, turned to a small research company based in New Jersey — Celgene — that agreed to make the drug, whose patent had expired.

Initially, the drug seemed to help manage wasting syndrome and oral ulcers in people living with HIV. While other drugs are now being used to treat those conditions, researchers still believe Thalidomide holds potential for those with HIV who don’t respond well to corticosteroids like prednisone.

In 2006, it was approved for use as a therapy for newly diagnosed multiple myeloma patients, and another version of Thalidomide is about to be approved — Pomalidomide — that will replace the current
version, Revlimid, said Lister.

“It has fewer side effects but they exist nonetheless,” he said, citing sleepiness, peripheral neuropathy and a decrease in white blood cell counts. And while birth defects are always a concern, the newer versions of Thalidomide aren’t used on patients who are very young, he added. “It’s not often that you see a patient with multiple myleoma in their teens or 20s, but of course pregnancy is certainly a concern if they were to be exposed to these agents.”

Booth, a native of Jamaica, is unpersuaded.

Thalidomide continues to reveal pernicious effects on survivors and the compensation fund established in the U.K. — his mother took the drug while living in England — isn’t nearly enough to see these victims into old age.

While German and English victims who receive compensation are prohibited from suing Grunenthal under the terms of the settlement, an Australian lawsuit is under way, and in September, a U.S. law firm announced it was going to court on behalf of 11 American victims and is soliciting more.

While Booth, a nationally renowned artist and professor, receives some compensation from the U.K. fund, he must continue to work full time for a living in order to support himself and his two sons, even while struggling with a deteriorating shoulder and health problems experienced by many Thalidomide survivors — many of whom were born with malformed or missing internal organs.
Treatment has confounded doctors, many of whom have never seen these kinds of cases — because Thalidomide babies never existed before the 1950s.

In January, Booth persuaded a renowned Philadelphia surgeon to perform surgery on his right shoulder, which has no socket and after years of strenuous use, had bone fragments embedded in the tissue. He is still in recovery, but new complications have arisen, including bone spurs and other unintended consequences.

Thalidomide “was a terrible invention that caused untold amounts of physical and emotional damage,” he said in an interview from his home in Easton, Lehigh County. “Now it is now being promoted as a ‘comeback’ drug because of limited use with specific kinds of cancer as a late-stage treatment. While I understand the desperation and need of those afflicted with cancer, I will never be able to accept that a drug with Thalidomide’s record is still a viable solution to anything.”