The "children of thalidomide" in Billy Joel's song "We Didn't Start the Fire" were

10,000 babies born with shortened arms and legs or without any limbs at all. Their
mothers had taken the drug thalidomide early in their pregnancies to help them sleep
and to keep them from feeling nauseated.
Of the 10,000 babies with "seal-like" limbs, only seventeen were born in the United
States. The number was low because Dr. Frances Kelsey blocked the sale of the drug in
this country.
Now, some thirty years later, thalidomide has resurfaced. Doctors are investigating its
potential as a treatment for a variety of diseases.

A drug company in Germany developed thalidomide in the 1950s as a sleeping pill.

Sales boomed because the drug was cheap, seemed to be safe even when taken in large
quantities, and apparently caused no harm to experimental animals. The company
wanted to sell thalidomide in the United States. So, in 1960, the company applied to the
Food and Drug Administration (FDA) for approval, because the safety of all drugs must
be reviewed by this agency before they can be sold in the United States.
Given thalidomide's popularity in Europe, FDA officials thought that approval for the
drug would be simple and straightforward. They gave the folder on thalidomide to Dr.
Kelsey -- their newest medical reviewer -- expecting approval to be routine.
From the start, Kelsey refused to be hurried into approving the sale of thalidomide. She
felt strongly that, even though the drug was in use all over Europe, too little information
was known about its side effects. Kelsey found it peculiar that the drug affected experimental animals differently from humans. While thalidomide had no reported harmful
effects on the animals, it also did not have the beneficial effect of making them sleepy.
Refusing to take "no" for an answer and eager to sell their product, the drug
manufacturers pressured Kelsey, but she stood her ground. She would not give
thalidomide her stamp of approval until she had better proof of its safety.
Then, in February 1961, Kelsey read in the British Medical Journal that thalidomide
could have harmful effects. A British physician reported that long-term use of
thalidomide caused tingling, numbness,and burning pain in the fingers and toes, and he
speculated that thalidomide damaged nerves in those parts of the body.

For Kelsey, this report raised a red flag. She suspected that a drug that damaged nerves
could have wide-ranging effects on a developing fetus. In graduate school, Kelsey had
been intrigued by teratogens, drugs that harm the fetus, and she suspected that
thalidomide was one of them.
In November 1961, a German doctor reported that thalidomide caused birth defects, and
the drug was taken off the German market. Soon after, the drug manufacturers formally
withdrew their application for approval in the United States.
On July 15, 1962, a reporter celebrated Kelsey on the front page of the Washington Post
as the "heroine...[whose] skepticism and stubbornness...prevented what could have been
an appalling American tragedy, the birth of hundreds or indeed thousands of armless and
legless children (1)."
Just a few American women gave birth to "thalidomide babies;" they were the ones who
had taken the drug while participating in investigational studies or had gotten it in other
countries.
As the gatekeeper who had prevented thalidomide's
widespread distribution, Kelsey received the highest award
Kelsey receives the Gold Medal for federal civilian service from President Kennedy. A New
for Distinguished Civilian Service York Times front-page article on August 5, 1962 praised
from President Kennedy in 1962.
Kelsey for leading "a two-year battle with the makers of
Courtesy of the National
thalidomide (2)."
Library of Medicine.

Thalidomide was not completely shelved after the 1960s tragedy. In 1965, an Israeli
doctor used it to treat a patient who had leprosy. He had given the man a drug to fight
the bacteria that cause the disease. The drug induced an extremely uncomfortable
inflammatory reaction. To ease the patient's discomfort and help him sleep, the doctor
then gave him thalidomide. The patient slept well and, in addition, thalidomide brought
the inflammation under control. This second effect was "dumb luck or pure serendipity,"
says Dr. Lawrence Fox, who is now studying some of thalidomide's other effects. The
Israeli observation led doctors to begin studying thalidomide's use in treating
inflammatory diseases.
Today, stories about new uses for thalidomide are springing up in magazines and newspapers, because more patients than ever are receiving the drug in investigational studies,
says Dr. Deborah Birnkrant of the FDA. "Thalidomide Returns, Now to Treat AIDS," a
recent headline in the Boston Globe announced (3). "Oldest Horrors of Thalidomide
Give Way to New Medical Hopes" reads a headline in the New York Times (4).
Scientists are beginning to understand better how thalidomide works in the body. And,
as they learn more about what parts of the body and what biological processes are
affected by thalidomide, they can test the drug as a treatment for other diseases and
conditions. Birnkrant cautions that there is still "no place in a medicine cabinet for
thalidomide unless a patient has a serious, life-threatening, or unresponsive condition,

where the physician, the FDA, and the patient agree that the benefits of thalidomide
outweigh the risks."
In particular, doctors believe the drug may be beneficial for treating illnesses that
involve inflammations, the painful conditions in which tissues are damaged, get red and
hot, and swell up. For example, thalidomide seems to help patients who suffer from
arthritis, an inflammation of the joints. Fox discovered that thalidomide heals mouth
and throat sores in people infected with HIV, the virus that causes AIDS (5). These sores
make eating extremely painful, and, when patients cannot eat, they become thin, frail,
and even more vulnerable to infection.
Fox, like Birnkrant, cautions that thalidomide must only be "administered by a
physician who is vigilant for the possible serious side effects." Thalidomide irreversibly
damages nerves in the fingers and toes. Such damage can be extremely painful and can
lead to problems with muscle control, such as difficulty walking. One patient described
feeling as though his foot were sealed in a metal shoe. In addition, because the drug is
unquestionably teratogenic, doctors carefully monitor women of child-bearing age who
are involved in research studies and caution them not to become pregnant during the
study period.

The story of a doctor accidentally finding that a drug has unexpected benefits is fairly
common, says Dr. John Decker, an emeritus scientist at NIH who formerly directed its
research hospital. Decker cites the example of a doctor in Paris who injected his patient
with gold in the early 1900s to treat tuberculosis. The patient also had arthritis.
Unexpectedly, the gold injections reduced the swelling and redness in the patient's
joints. Gold injections later became a standard treatment for arthritis. Today, doctors still
use gold, although in a more refined form, to treat arthritis.
Billy Joel inadvertently made an accurate prediction when he sang of thalidomide in
"We Didn't Start the Fire:" today, doctors are using thalidomide to extinguish the flames
of discomfort in patients who have inflammation -- a word that means "setting on fire."

1. Washington Post, July 15, 1962.

2. New York Times, August 5, 1962.
3. Boston Globe, May 22, 1997.
4. New York Times, December 28, 1995.
5. New England Journal of Medicine, May 22, 1997, 336(21): 1487-1493.
6. Chemically Induced Birth Defects, James L. Schardein (Marcel Dekker, Inc.,
NY: 1985).
7. Drugs as Teratogens, James L. Schardein (CRC Press, Cleveland: 1976).
8. Teratogens: Chemicals Which Cause Birth Defects, Vera M. Kolb, Ed.
(Elsevier, Amsterdam: 1993).
9. Clio Medica 1976, 11(2): 79-93.

U.S. Food and Drug Administration

FDA Consumer magazine
March-April 2001

Frances Oldham Kelsey: FDA

Medical Reviewer Leaves Her Mark
on History
By Linda Bren
It was early 1942 and war was raging in the jungles of the Pacific. In addition
to fighting the Japanese, Allied troops found themselves under attack by
malaria-carrying mosquitoes. And since enemy soldiers had already captured
several plantations of cinchona trees, the source of the anti-malarial quinine,
the search was on for an effective quinine substitute to combat the disease. A
possible treatment--in the form of a dark, inky substance--arrived for testing in
the pharmacology department at the University of Chicago. Pharmacologist
Frances Oldham Kelsey, like many other university researchers throughout
the country, had enlisted in the search for synthetic cures for malaria.
As it turned out, the inky substance had been sent by a veterinarian in Texas.
"He said that he had just tried it on his secretary without ill effects," says
Kelsey, "and he planned next to try it on cattle. It showed the relative value
placed on women and cattle in Texas at that time," Kelsey says with
amusement. The good humor and equanimity Kelsey displays at this slight
are symptomatic of the way she approached most of life's adversities.
The war ended without finding a good substitute for quinine. But Kelsey did
learn something valuable from the experience. She learned that rabbits
metabolized quinine rapidly, but pregnant rabbits had less ability to break
down the drug, and embryonic rabbits could not break it down at all. She also
learned that drugs could pass through the placental barrier between mother
and unborn child. These insights would serve Kelsey well some 15 years later
when in early 1960, as a new Food and Drug Administration employee, she
was asked to evaluate a drug most thought was harmless. That drug was
thalidomide.
Although pressured by the manufacturer to quickly approve a drug already in
widespread use throughout the rest of the world, Kelsey held her ground.
When she repeatedly asked for more data and effectively forestalled the
approval of thalidomide, Kelsey did more than keep a dangerous drug off the
market. She set into motion a series of events that would forever change the
way drugs are tested, evaluated, and introduced in America.
In recognition of Kelsey's vigilance, President John F. Kennedy, on Aug. 7,
1962, presented her with the highest honor that can be bestowed upon a U.S.
civilian: the medal for Distinguished Federal Civilian Service. And nearly 40

years later, Kelsey was once again honored. On Oct. 7, 2000, she was
inducted into the National Women's Hall of Fame in Seneca Falls, N.Y. Kelsey
joins such other women of distinction in the Hall as American Red Cross
founder Clara Barton, first American woman physician Elizabeth Blackwell,
and human rights activist and first lady Eleanor Roosevelt.

The Thalidomide Tragedy

All they wanted was a good night's sleep, and a drug called thalidomide gave
it to them. It brought a quick, natural sleep for millions of people who had
trouble drifting off, and it also gave pregnant women relief from morning
sickness. The drug's German manufacturer claimed it was non-addictive,
caused no hangover, and was safe for pregnant women. And, unlike
barbiturates, its lack of toxicity made it a poor choice for a suicide attempt.
By 1957, thalidomide was sold over-the-counter in Germany. By 1960, it was
sold throughout Europe and South America, in Canada, and in many other
parts of the world. To introduce it into the United States, the RichardsonMerrell pharmaceutical company of Cincinnati submitted an application to
FDA in September 1960 to sell thalidomide under the brand name Kevadon.
The application was assigned to medical officer Kelsey, who had joined FDA
just one month earlier. It was her first drug review assignment.
Under the law at that time, FDA had 60 days to review a drug application. If
an FDA medical officer notified the company that the application was
incomplete, it was considered withdrawn and the company would have to
resubmit it with additional data. With each resubmission, the 60-day clock
would start again.
Kelsey had concerns about the drug from the beginning. So did the
pharmacologist and chemist who assisted Kelsey in the drug review. The
chronic toxicity studies were not long enough, the absorption and excretion
data were inadequate, and the manufacturing controls had shortcomings. "We
were concerned about the non-absorption," says Kelsey. "That you could give
enormous amounts, both to animals and humans, without toxicity. We felt that
there might be conditions, illnesses, or other drugs that might change the
absorption, and toxic effects might appear." After Kelsey detailed these
deficiencies in a letter to Richardson-Merrell, the company sent in additional
information--but not enough to satisfy Kelsey.
"The clinical reports were more on the nature of testimonials," says Kelsey,
"rather than the results of well-designed, well-executed studies."
Kelsey continued to request more data to show the drug's safety, and with
each request, the 60-day clock restarted. Dr. Joseph Murray, RichardsonMerrell's representative, grew increasingly frustrated. He made repeated
phone calls and personal visits to Kelsey, and complained to her superiors
that she was unreasonable and nit-picking, and that she was delaying the
drug's approval unnecessarily.

But Kelsey did not cave under the pressure.

"I think I always accepted the fact that one was going to get bullied and
pressured by industry," says Kelsey. "It was understandable that the
companies were very anxious to get their drugs approved."
Richardson-Merrell may have been "over-eager," Kelsey admits. "They were
particularly disappointed because Christmas is apparently the season for
sedatives and hypnotics (sleeping pills). They kept calling me, and then just
came right out and said, 'We want to get this drug on the market before
Christmas, because that is when our best sales are.'"
In December of 1960, three months after Richardson-Merrell submitted its
application, the British Medical Journal published a letter from a physician,
Leslie Florence, who had prescribed thalidomide to his patients. Florence
reported seeing cases of peripheral neuritis, a painful tingling of the arms and
feet, in patients who had taken the drug over a long period of time.
After reading the journal letter, Kelsey immediately contacted RichardsonMerrell, requesting further information on this serious side effect. Recalling
how quinine had affected adult rabbits and fetuses differently, Kelsey
wondered what effects thalidomide may have if used during pregnancy. She
suspected that a drug that could damage nerves could also affect a
developing fetus. Her suspicions soon proved to be grimly accurate.
European physicians began reporting a disturbing phenomenon. A growing
number of women were giving birth to terribly deformed babies. Some had
abnormally short limbs, with toes sprouting directly from the hips, and flipperlike arms--a condition known as phocomelia. Others had malformed internal
organs or eye and ear defects. Women were miscarrying or giving birth to
infants who died shortly after.
At first, no one knew the cause. But by November 1961, a German
pediatrician, Widukind Lenz, determined it was thalidomide. Upon questioning
his patients, Lenz found that 50 percent of the mothers with deformed
children had taken thalidomide in the first trimester of pregnancy.
Lenz warned the German manufacturer, Chemie Grunenthal, about the
dangers of thalidomide. Ten days later, German health authorities pulled the
drug from the market--against the company's wishes. Other countries closely
followed its lead. Chemie Grunenthal continued to dispute the findings, but in
March 1962, Richardson-Merrill withdrew its application from FDA.
Unfortunately, by then, it was too late for many.
More than 10,000 children in 46 countries were estimated to have been born
with deformities as a consequence of thalidomide use. The damage in the
United States was small by comparison, but no less devastating to the 17
children born in America with thalidomide-associated deformities.

Richardson-Merrell had distributed more than 2.5 million thalidomide tablets

to more than 1,000 doctors throughout the United States on what was called
an investigational basis. The doctors, in turn, gave thalidomide to nearly
20,000 patients, several hundred of whom were pregnant women.
FDA's field staff located the doctors who had been given thalidomide and
urged them to contact patients who had been given the drug. But not all of the
doctors kept records of the drug's distribution. Through news releases, FDA
warned women of the danger of taking the drug, but it is unlikely that all of
these women were reached.

Kelsey's Early Career

Born in 1914 in Cobble Hill on Vancouver Island, British Columbia, Kelsey
grew up in the country where she collected everything from bugs to bird eggs.
"I always knew I'd be some kind of scientist," she says.
Graduating from high school at age 15, Kelsey went on to earn a BSc in 1934
from McGill University in Montreal. She then hoped to work in a laboratory,
but it was the depth of the Depression and men were selected to fill the few
openings that existed. "This situation led me to realize that my choices were
either to do graduate studies or to join the bread line," says Kelsey. "I decided
graduate work would be more interesting."
After earning her MSc at McGill in pharmacology in 1935, Kelsey, on her
professor's urging, wrote to E. M. K. Geiling, MD. Geiling, a noted researcher,
was starting up a new pharmacology department at the University of Chicago.
When Kelsey read Geiling's letter offering her a research assistantship and
scholarship in the PhD program at Chicago, she was delighted. But there was
one slight problem--one that "tweaked her conscience a bit."
The letter began "Dear Mr. Oldham," Oldham being her maiden name. Kelsey
asked her professor at McGill if she should wire back and explain that
Frances with an "e" is female. "Don't be ridiculous," he said. "Accept the job,
sign your name, put 'Miss' in brackets afterwards, and go!"
So Kelsey went. She left Montreal and moved to Illinois.
"To this day, I do not know if my name had been Elizabeth or Mary Jane,
whether I would have had that first big step up," says Kelsey. "And to his
dying day, Professor Geiling would never admit one way or the other."
In 1937, Kelsey's second year at the University of Chicago, FDA asked
Geiling to help determine why people were dying after they drank "Elixir
Sulfanilamide." Sulfanilamide, introduced in 1935, was extremely effective in
fighting bacterial infections. But the sulfanilamide pills were pretty
unpalatable. One manufacturer, the S. E. Massengill Company of Bristol,
Tennessee, asked its chemist to find a liquid solution in which the drug could
be dissolved, making it more pleasant-tasting, especially to children.

"The solution was put right on the market with a little pink coloring and a little
cherry flavoring, and it sold like wildfire," says Kelsey. Under the law at that
time, the Food and Drugs Act of 1906, a company could sell a drug without
showing its safety.
Soon after the elixir hit the market, reports of deaths involving the solution
started flowing in--but no one was sure whether it was the sulfanilamide or the
solvent that was toxic.
As a student of Geiling, Kelsey helped conduct animal studies to find out
which was the toxic element. After testing various combinations of
sulfanilamide and solvent, it became apparent that the toxin was the solvent-diethylene glycol--which is similar to antifreeze.
The immediate outcome of Elixir Sulfanilamide was tragic--it caused 107
deaths, many of them in children. It also led to the suicide of Massengill's
chemist and to a fine of $26,100 levied against Massengill, the highest that
was legally allowed at the time. Since the manufacturer was not required to
demonstrate its product's safety, FDA could not hold Massengill accountable
for the deaths. The company could only be fined for "misbranding" its product.
An elixir, by definition, contained alcohol, but there was no alcohol present in
Elixir Sulfanilamide.
The long-term effects were also remarkable. Public outrage spurred the
passage of the Federal Food, Drug, and Cosmetic Act of 1938. The new drug
law required companies to show evidence of safety before their product could
be marketed, and warnings of the potential hazards of drugs were required.
And for the first time, medical devices and cosmetics were included in FDA's
authority.
In the same year the new drug law went into effect, Kelsey received her PhD
in pharmacology from the University of Chicago and joined the faculty. Later,
in 1943, she met and married another faculty member, Dr. Fremont Ellis
Kelsey. While in medical school, she gave birth to her two daughters.
In the decade after earning her MD at Chicago in 1950, Kelsey held jobs
reviewing articles for the Journal of the American Medical Association and
teaching pharmacology at the University of South Dakota. She also worked
as a temporary doctor in a number of small communities throughout that
state. In 1960, Kelsey was offered a position at FDA in Washington, D.C. It
was there that she would leave her mark on history.

The Road to Stronger Drug Laws

The headline read "'Heroine' of FDA Keeps Bad Drug Off of Market." The
story appeared on the front page of The Washington Post on July 15, 1962.
Reporter Morton Mintz told the tale of "how the skepticism and stubbornness
of a Government physician prevented what could have been an appalling
American tragedy, the birth of hundreds or indeed thousands of armless and
legless children."

Mintz's article catapulted Kelsey to stardom. It also inspired a flurry of followup articles on drug control in The New York Times, Saturday Review, Life, and
other mainstream media of the day.
In the wake of the furor these articles created, the American public soon came
to realize how narrowly they had averted a major tragedy. And politicians who
had been fighting for years for tighter drug controls were finally taken
seriously. A controversial bill introduced by Sen. Estes Kefauver of Tennessee
several years earlier was resurrected from its congressional committee
graveyard and rewritten. President Kennedy signed the bill generally known
as the Kefauver-Harris Amendments into law on Oct. 10, 1962. This landmark
drug law, which modified the earlier Federal Food, Drug, and Cosmetic Act of
1938, strengthened FDA's control of drug experimentation on humans and
changed the way new drugs were regulated.
Under the 1938 law, drug manufacturers had only to show that their drugs
were safe. Under the 1962 law, for the first time, they also had to show that all
new drugs were effective. Kelsey was there for both of them. She participated
in the creation of two of the most important public health laws in the nation's
history. But she was no orator or visionary or politician. She was simply a
scientist trying to understand what had happened and how the public health
could be protected.
The 1962 amendments required informed consent from patients used in drug
studies, and sponsoring drug companies were required to report to FDA any
adverse reactions to the drug. FDA made Kelsey head of its investigational
drug branch, created to evaluate and monitor clinical trials for compliance with
these new drug regulations.
FDA grew along with its increased regulatory responsibilities. In 1960, Kelsey
was one of only seven full-time and four young part-time physicians reviewing
drugs at the agency. Today there are nearly 400 medical officers at FDA, but
they are not as accessible to the drug companies as they were in the 1960s
when Kelsey was pressured by the thalidomide manufacturer. "Medical
officers today are insulated from the drug company by the consumer safety
officer and project manager staff," says Janet Woodcock, MD, director of
FDA's Center for Drug Evaluation and Research (CDER).
Kelsey continues to persevere in safeguarding public health. At age 86, she
serves as deputy of scientific and medical affairs in CDER's office of
compliance.
Though Kelsey, from the time she was a little girl, always knew she would be
"some kind of scientist," she never foresaw the role she would play in the
history of drug law. Her efforts in two events--the testing of Elixir
Sulfanilamide and the prevention of thalidomide's approval--led to turning
points in the nation's drug regulations and the federal government's role as
protector of public health.

"It has been an interesting career," says Kelsey, in her understated manner.
And of her first drug review assignment at FDA in 1960--the thalidomide
application--she notes, "They gave it to me because they thought it would be
an easy one to start on. As it turned out, it wasn't all that easy."

Thalidomide Today
Thalidomide never disappeared. Since the discovery in the 1960s of its ability
to cause birth defects, the drug has continued to be studied throughout the
world to treat cancer and other life-threatening or disabling conditions. FDA
approved the drug for the first time in this country in 1998 under the brand
name Thalomid, manufactured by Celgene Corporation of Warren, N.J. It was
approved for one condition only: erythema nodosum leprosum (ENL), a
severe and debilitating complication of leprosy (Hansen's disease).
Because of the dangers the drug still presents to the unborn, FDA took
unprecedented regulatory steps to control Thalomid's marketing. Extensive
patient education about risks, a patient registry of those taking the drug, and
mandatory pregnancy testing at least monthly for sexually active women of
childbearing age are all part of the program to prevent another thalidomide
tragedy.
Thalidomide continues to be evaluated in similarly controlled FDA-approved
studies. The drug inhibits the growth of new blood vessels in tumors, and has
shown the most promise in treating multiple myeloma (a cancer of the bone
marrow) and Kaposi's sarcoma (an AIDS-related cancer), says William Figg,
PharmD, a senior investigator at the National Cancer Institute. Thalidomide
has also shown potential to treat solid tumors in the prostate and brain, as
well as graft-versus-host disease, a complication of bone marrow transplants.
Kelsey served on FDA's working group, formed in 1994, to develop and
implement uniform standards of safety for clinical studies using thalidomide.
"She provided this moral and scientific backbone to the group, given her
previous experience with the drug," says Debra Birnkrant, MD, the working
group's chairperson.
Kelsey knows that thalidomide can give relief to patients with leprosy and
perhaps other diseases, but is concerned about its widespread use-particularly with the availability of Internet sales. "We need to take
precautions," she says, "because people forget very soon."
--L.B.
For more information about thalidomide, see commentary "Living in a World
With Thalidomide: A Dose of Reality," in this issue.