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04/03/2001

Thank You, Dr. Kelsey

In last week''s column on factors motivating positive responses to
requests, I missed the obvious ploy used all the time in ads and
commercials - sex! After posting the column, I watched an
episode of Raymond in which a lovely young blond woman in a
low-cut blouse arrived at the door to demonstrate the latest in
vacuuming technology to Raymond and brother Robert. When
Raymond''s wife returned, she found him vacuuming up a storm
with the new vacuum cleaner, and general hilarity ensued.

The March-April 2001 issue of FDA Consumer magazine has a
portrait of another lovely woman on its cover. Not a sexy young
blond, but an 86-year old employee of the Food and Drug
Administration. A very pleasant looking woman, Dr. Frances
Oldham Kelsey is deputy of scientific and medical affairs in the
office of compliance of the FDA''s Center for Drug Evaluation
and Research. Last year, she joined such women as Eleanor
Roosevelt, Rachael Carson, Clara Barton, and Ella Fitzgerald in
the National Women''s Hall of Fame. Some of you able-bodied
readers in your early 40s might literally owe your very existence
or your able body to this woman. Her primary contribution, for
which she received the medal for Distinguished Federal Civilian
Service from President Kennedy in 1962, involved a drug that
proved responsible for one of the major medical tragedies of the
last century.

Let''s look at her life prior to joining the FDA. A native of
Canada, she got her Bachelors degree from McGill University in
Montreal. The Depression was in full swing and jobs for women
were few, motivating her to pursue graduate work at McGill,
where she got her Masters degree in pharmacology in 1935. Her
professor urged her to apply for a position at the University of
Chicago, where a Dr. Geiling was setting up a pharmacology
department. Dr. Geiling responded positively, but his letter
offering her a research assistantship and a scholarship started
with "Dear Mr. Oldham," (Oldham was her maiden name). Dr.
Geiling appeared unaware that Frances with a "e" has a female
connotation. Today, Kelsey still wonders about her acceptance if
her name had more obviously denoted her sex.

A harbinger of things to come, Kelsey found herself involved in
controversy when Dr. Geiling asked her to assist in answering a
request from the FDA. The drug sulfanilamide had been
introduced in 1935 and was very effective in countering bacterial
infections. Its bad taste prompted the manufacturer to ask its
chemist found a solvent, which he did. The drug was dissolved
in the solvent and some coloring and cherry syrup were added.
The product was called Elixir Sulfanilamide. Tragically, the
tasty concoction caused the deaths of over a hundred people,
including many children, and the chemist ended up committing
suicide. Kelsey''s job for the FDA was to run animal studies to
determine the culprit, which she found to be the solvent,
diethylene glycol, also used in antifreeze.

The public uproar over the incident prompted the enactment of
the Federal Food, Drug and Cosmetic Act of 1938. Until that
time, drug companies were not required to demonstrate the safety
of a drug prior to marketing it. Indeed, the manufacturer of
Elixir Sulfanilamide was only fined the maximum allowed,
$21,100, and that was for "misbranding" the product. Even that
fine was only justified because an "elixir" was supposed to
contain alcohol, and there was none in the product. Imagine the
lawsuits and damages had this occurred today!

Kelsey''s time at Chicago was quite productive. She got her
Ph.D. in pharmacology in 1938, became a member of the faculty,
married a fellow faculty member, had two daughters and got her
MD in 1950. During that period, there was the matter of World
War II. In the Pacific, Allied troops were encountering malaria-
bearing mosquitoes. The Japanese had captured plantations of
cinchona trees, from which the antimalarial drug quinine was
derived. Kelsey was one of those engaged in what proved an
unsuccessful quest to find a substitute for quinine. However, she
found that though rabbits metabolized quinine rapidly, pregnant
rabbits had more difficulty and couldn''t break down the drug
easily. She also found that quinine could pass through the
placental barrier separating the mother rabbit and the fetus,
which couldn''t break down the drug at all.

Fast forward to 1960, when Kelsey accepted a job at the FDA.
After only one month, this new employee was given her first
assignment - to review a drug application. The drug was
thalidomide. At that time, thalidomide was considered quite
benign. It was being sold all over Europe, South America,
Canada and other parts of the world and in Germany was even
sold over the counter. It was widely prescribed as a sleeping pill
and as an agent for relief of morning sickness during pregnancy.
Its German manufacturer claimed it to be non-addictive, non-
toxic and safe for pregnant women. It must have looked like the
drug that would easily sail through the evaluation process. But
Kelsey and her assistant in the evaluation process had concerns.

One result in the submitted tests was that large amounts of the
drugs could be given to animals and humans without them
absorbing the drug. Kelsey was concerned that there could be
conditions or perhaps drug interactions that might change this
non-absorption feature and that toxicity could result. Then, three
months into the review process, a British doctor published an
article saying that some patients who had taken the drug over a
prolonged period of time had a painful tingling of the arms and
feet. Kelsey thought back to her rabbit work and wondered if a
drug that could affect the nerves, causing the tingling, could be
transmitted to and affect the fetus in some harmful way.

In those days, there was a 60-day time limit for the FDA to
review a drug - not much time! But, every time an application
was sent back as incomplete, the 60-day clock started over again.
Kelsey kept returning the application to the company, restarting
the clock each time. Company representatives at that time had
direct access to the reviewer, and considerable pressure was
applied on Kelsey and on her superiors to get her to approve the
drug. In fact, the company had distributed over 2 million
thalidomide tablets to some 1,000 doctors on an "investigational"
basis. Kelsey did not fold under the pressure.

Soon, Europe found itself experiencing a rash of babies being
miscarried or born with awful deformities - abnormally short
limbs, flipper-like arms, toes growing directly from the hips and
other serious malformations. It wasn''t until November of 1961
that a German pediatrician found that half of the mothers of
deformed babies had taken thalidomide in the first trimester of
their pregnancy. It took German health authorities only 10 days
to pull thalidomide from the market. It took until March of 1962
for the sponsoring company to pull its application from the FDA!

Some 10,000 deformed babies worldwide were born with defects
attributed to thalidomide use. Thanks to Dr. Kelsey and the
FDA''s public warnings and its tracking down of doctors who had
received the "investigational" thalidomide, only 17 thalidomide
babies were born in the United States. The July 15, 1962
Washington Post''s front page headline was "''Heroine'' of FDA
Keeps Bad Drug Off of Market."

Kelsey became a celebrity and, as with the Elixir Sulfanilamide,
her work contributed to a major revision of the regulation of the
process of introducing new drugs to the marketplace. The
Kefauver-Harris Amendments were enacted and signed into law
by President Kennedy on October 10, 1962. Drug manufacturers
not only had to show their drugs were safe, but also effective.
Informed consent was required for patients in drug trials and
sponsoring drug companies were required to report to the FDA
any adverse reactions to their drug. Kelsey was put in charge of
a new unit charged with evaluating and monitoring clinical drug
trials to ensure compliance with the new regulations.

Almost four decades later, thalidomide and Dr. Kelsey are still
around. In 1998, thalidomide was approved for use in the U.S.
solely for the treatment of a severe complication of Hansen''s
disease (leprosy). However, the drug also shows promise for
treating various types of cancers and tumors. AIDS-related
wasting and cancer are active areas of research and clinical trials
are underway. Strict controls of the prescribing and dispensing
of thalidomide are in place. Kelsey, who doesn''t seem to want
to retire, has been involved in establishing strict regulatory steps
to prevent thalidomide from falling into the hands of pregnant
women.

I visited the Web site of one supplier of the drug and found that it
can only be prescribed and dispensed by doctors and pharmacists
registered with a restricted distribution program. Furthermore,
both male and female patients must sign agreements that they
will follow strictly certain conditions in any sexual contacts.
For example, women of childbearing potential must employ two
simultaneous contraceptive measures and have pregnancy tests
just before and at prescribed intervals after starting the drug.
Even if they''ve had a vasectomy, male patients must use
condoms with partners of childbearing potential. Sex is serious
business for these patients.

On a lighter note, when Kelsey was at Chicago, a veterinarian
from Texas submitted a substance to test for possible antimalarial
properties. He said he''d tried it on his secretary with no ill
effects and planned next to try it on his cattle! Today, Kelsey
smiles at that Texan''s rating of the value of women versus cattle.

Allen F. Bortrum



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-04/03/2001-      
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Dr. Bortrum

04/03/2001

Thank You, Dr. Kelsey

In last week''s column on factors motivating positive responses to
requests, I missed the obvious ploy used all the time in ads and
commercials - sex! After posting the column, I watched an
episode of Raymond in which a lovely young blond woman in a
low-cut blouse arrived at the door to demonstrate the latest in
vacuuming technology to Raymond and brother Robert. When
Raymond''s wife returned, she found him vacuuming up a storm
with the new vacuum cleaner, and general hilarity ensued.

The March-April 2001 issue of FDA Consumer magazine has a
portrait of another lovely woman on its cover. Not a sexy young
blond, but an 86-year old employee of the Food and Drug
Administration. A very pleasant looking woman, Dr. Frances
Oldham Kelsey is deputy of scientific and medical affairs in the
office of compliance of the FDA''s Center for Drug Evaluation
and Research. Last year, she joined such women as Eleanor
Roosevelt, Rachael Carson, Clara Barton, and Ella Fitzgerald in
the National Women''s Hall of Fame. Some of you able-bodied
readers in your early 40s might literally owe your very existence
or your able body to this woman. Her primary contribution, for
which she received the medal for Distinguished Federal Civilian
Service from President Kennedy in 1962, involved a drug that
proved responsible for one of the major medical tragedies of the
last century.

Let''s look at her life prior to joining the FDA. A native of
Canada, she got her Bachelors degree from McGill University in
Montreal. The Depression was in full swing and jobs for women
were few, motivating her to pursue graduate work at McGill,
where she got her Masters degree in pharmacology in 1935. Her
professor urged her to apply for a position at the University of
Chicago, where a Dr. Geiling was setting up a pharmacology
department. Dr. Geiling responded positively, but his letter
offering her a research assistantship and a scholarship started
with "Dear Mr. Oldham," (Oldham was her maiden name). Dr.
Geiling appeared unaware that Frances with a "e" has a female
connotation. Today, Kelsey still wonders about her acceptance if
her name had more obviously denoted her sex.

A harbinger of things to come, Kelsey found herself involved in
controversy when Dr. Geiling asked her to assist in answering a
request from the FDA. The drug sulfanilamide had been
introduced in 1935 and was very effective in countering bacterial
infections. Its bad taste prompted the manufacturer to ask its
chemist found a solvent, which he did. The drug was dissolved
in the solvent and some coloring and cherry syrup were added.
The product was called Elixir Sulfanilamide. Tragically, the
tasty concoction caused the deaths of over a hundred people,
including many children, and the chemist ended up committing
suicide. Kelsey''s job for the FDA was to run animal studies to
determine the culprit, which she found to be the solvent,
diethylene glycol, also used in antifreeze.

The public uproar over the incident prompted the enactment of
the Federal Food, Drug and Cosmetic Act of 1938. Until that
time, drug companies were not required to demonstrate the safety
of a drug prior to marketing it. Indeed, the manufacturer of
Elixir Sulfanilamide was only fined the maximum allowed,
$21,100, and that was for "misbranding" the product. Even that
fine was only justified because an "elixir" was supposed to
contain alcohol, and there was none in the product. Imagine the
lawsuits and damages had this occurred today!

Kelsey''s time at Chicago was quite productive. She got her
Ph.D. in pharmacology in 1938, became a member of the faculty,
married a fellow faculty member, had two daughters and got her
MD in 1950. During that period, there was the matter of World
War II. In the Pacific, Allied troops were encountering malaria-
bearing mosquitoes. The Japanese had captured plantations of
cinchona trees, from which the antimalarial drug quinine was
derived. Kelsey was one of those engaged in what proved an
unsuccessful quest to find a substitute for quinine. However, she
found that though rabbits metabolized quinine rapidly, pregnant
rabbits had more difficulty and couldn''t break down the drug
easily. She also found that quinine could pass through the
placental barrier separating the mother rabbit and the fetus,
which couldn''t break down the drug at all.

Fast forward to 1960, when Kelsey accepted a job at the FDA.
After only one month, this new employee was given her first
assignment - to review a drug application. The drug was
thalidomide. At that time, thalidomide was considered quite
benign. It was being sold all over Europe, South America,
Canada and other parts of the world and in Germany was even
sold over the counter. It was widely prescribed as a sleeping pill
and as an agent for relief of morning sickness during pregnancy.
Its German manufacturer claimed it to be non-addictive, non-
toxic and safe for pregnant women. It must have looked like the
drug that would easily sail through the evaluation process. But
Kelsey and her assistant in the evaluation process had concerns.

One result in the submitted tests was that large amounts of the
drugs could be given to animals and humans without them
absorbing the drug. Kelsey was concerned that there could be
conditions or perhaps drug interactions that might change this
non-absorption feature and that toxicity could result. Then, three
months into the review process, a British doctor published an
article saying that some patients who had taken the drug over a
prolonged period of time had a painful tingling of the arms and
feet. Kelsey thought back to her rabbit work and wondered if a
drug that could affect the nerves, causing the tingling, could be
transmitted to and affect the fetus in some harmful way.

In those days, there was a 60-day time limit for the FDA to
review a drug - not much time! But, every time an application
was sent back as incomplete, the 60-day clock started over again.
Kelsey kept returning the application to the company, restarting
the clock each time. Company representatives at that time had
direct access to the reviewer, and considerable pressure was
applied on Kelsey and on her superiors to get her to approve the
drug. In fact, the company had distributed over 2 million
thalidomide tablets to some 1,000 doctors on an "investigational"
basis. Kelsey did not fold under the pressure.

Soon, Europe found itself experiencing a rash of babies being
miscarried or born with awful deformities - abnormally short
limbs, flipper-like arms, toes growing directly from the hips and
other serious malformations. It wasn''t until November of 1961
that a German pediatrician found that half of the mothers of
deformed babies had taken thalidomide in the first trimester of
their pregnancy. It took German health authorities only 10 days
to pull thalidomide from the market. It took until March of 1962
for the sponsoring company to pull its application from the FDA!

Some 10,000 deformed babies worldwide were born with defects
attributed to thalidomide use. Thanks to Dr. Kelsey and the
FDA''s public warnings and its tracking down of doctors who had
received the "investigational" thalidomide, only 17 thalidomide
babies were born in the United States. The July 15, 1962
Washington Post''s front page headline was "''Heroine'' of FDA
Keeps Bad Drug Off of Market."

Kelsey became a celebrity and, as with the Elixir Sulfanilamide,
her work contributed to a major revision of the regulation of the
process of introducing new drugs to the marketplace. The
Kefauver-Harris Amendments were enacted and signed into law
by President Kennedy on October 10, 1962. Drug manufacturers
not only had to show their drugs were safe, but also effective.
Informed consent was required for patients in drug trials and
sponsoring drug companies were required to report to the FDA
any adverse reactions to their drug. Kelsey was put in charge of
a new unit charged with evaluating and monitoring clinical drug
trials to ensure compliance with the new regulations.

Almost four decades later, thalidomide and Dr. Kelsey are still
around. In 1998, thalidomide was approved for use in the U.S.
solely for the treatment of a severe complication of Hansen''s
disease (leprosy). However, the drug also shows promise for
treating various types of cancers and tumors. AIDS-related
wasting and cancer are active areas of research and clinical trials
are underway. Strict controls of the prescribing and dispensing
of thalidomide are in place. Kelsey, who doesn''t seem to want
to retire, has been involved in establishing strict regulatory steps
to prevent thalidomide from falling into the hands of pregnant
women.

I visited the Web site of one supplier of the drug and found that it
can only be prescribed and dispensed by doctors and pharmacists
registered with a restricted distribution program. Furthermore,
both male and female patients must sign agreements that they
will follow strictly certain conditions in any sexual contacts.
For example, women of childbearing potential must employ two
simultaneous contraceptive measures and have pregnancy tests
just before and at prescribed intervals after starting the drug.
Even if they''ve had a vasectomy, male patients must use
condoms with partners of childbearing potential. Sex is serious
business for these patients.

On a lighter note, when Kelsey was at Chicago, a veterinarian
from Texas submitted a substance to test for possible antimalarial
properties. He said he''d tried it on his secretary with no ill
effects and planned next to try it on his cattle! Today, Kelsey
smiles at that Texan''s rating of the value of women versus cattle.

Allen F. Bortrum