ocumentary Examines Sulfanilamide Deaths of 1937

BETHESDA, MD, 05 December 2003 — In 1937, small-town physician Archie Calhoun

prescribed a new drug to several of his patients in Mount Olive, Mississippi.

But within days, many of Calhoun's 13 patients who were taking the medication—
including his best friend—had become gravely ill.

The drug was a newly marketed liquid form of sulfanilamide, a synthetic antibacterial
drug used to treat streptococcal infections.

Sulfanilamide, included in a class of drugs known as sulfonamides, or sulfa drugs, was

praised in the 1930s as the first product to successfully treat bacterial infections.

The drug received worldwide publicity after German pathologist Gerhard Domagk,
credited for discovering the antibacterial effects of the first sulfonamide drug, which was
marketed as Prontosil, and Swiss pharmacologist Daniel Bovet, acknowledged for
identifying that sulfanilamide killed strains of Streptococcus bacteria, won Nobel Prizes
in 1932 and 1936, respectively.

Americans first heard about the drug in 1936 when President Franklin D. Roosevelt's son
had been close to death from a severe sinus infection—a condition that could be fatal
during that era—until he was successfully treated with sulfanilamide.

"There has probably never been a single drug before or since that has had such a quick
acceptance," said historian Gene Davis in a documentary film scheduled to air on the
History Channel on December 11. "It was truly the first miracle drug of the 20th
Century."

Sulfanilamide was manufactured as tablets or as an injectable drug. Pharmaceutical

companies struggled with how to successfully liquefy the drug so that the product could
be marketed for children and patients who preferred to take their medications in liquid
forms.

But in 1937, Harold Watkins, chief chemist for pharmaceutical manufacturer S.E.
Massengill Co. in Bristol, Tennessee, discovered that he could use an industrial chemical
called diethylene glycol (DEG) as a dissolving agent for sulfanilamide.

DEG is used for keeping products, such as glue, cosmetics, and cigarettes, moist. Watkins
also added raspberry flavoring and red coloring to the product, which Massengill
marketed as Elixir Sulfanilamide, so that the medication would be more appealing for
children.

But DEG is a chemical cousin of antifreeze, and Watkins and his company failed to test
the product for safety before shipping 600 bottles of Elixir Sulfanilamide to pharmacies
and distributors and an additional 700 sample bottles to physician offices and Massengill
sales representatives.

"Elixir Sulfanilamide was essentially slapped together without a thought to testing,

without a thought to assessing its toxicity, or certainly without a thought to even looking
into literature to see what you were putting into the product," said Food and Drug
Administration (FDA) historian John Swann in the documentary Elixir of Death.

"The only thing they tried it out for was to see does it taste good, does it look good in a
bottle, did it look nice with a label on it," commented Davis in the film. "So they thought,
we've got the perfect product that we can ship all over the country."

Most of the bottles of the drug were distributed in Tulsa, Okalahoma, and in Mississippi.

But days after taking the first dose of the elixir, several patients died of kidney failure.

Tulsa physicians relayed a message to the American Medical Association about the
deaths, and the University of Chicago immediately launched a study to determine why
people were dying after ingesting Elixir Sulfanilamide.

Pharmacologist Frances Oldham Kelsey, who later worked for FDA and is credited for
keeping thalidomide off the market in the United States, helped conduct animal testing of
Elixir Sulfanilamide.

Kelsey, who appears in the documentary film, determined that DEG is a deadly poison.

"Typically the patients would report abdominal pain, nausea, vomiting, all sorts of
cramps, headaches, blindness, comatose or semicomatose condition, and they would
thrash about on the bed for days on end," said Davis. "The lucky ones were the ones that
lasted three or four days. The typical time of death would be about nine days."

It was an "extremely painful, excruciating death," he lamented.

After Massengill started getting reports about the deaths, the company issued a recall
telegram to pharmacists and physicians.

But the recall notice failed to warn that the elixir was lethal.

One of the pharmacists who received the recall telegram was Archie Calhoun's brother,
Graham, who quickly alerted the Mount Olive physician about the recall.

But for at least six of Calhoun's patients, including his friend, it was too late.

"Most of the time he was out on the road day and night tending to his patients," said
Davis. "He could not sleep, he could not eat. He is taking urine samples, he is taking
blood samples, he is trying to do the best that he can for them. But to his credit, he does
not try to deny any responsibility. If he knew his patients were going to die, he was going
to be honest with them and tell them that, because he thought they deserved to know."

FDA, an agency with little regulatory power in the 1930s, was alerted to the Elixir
Sulfanilamide deaths by an anonymous tip, Davis said.

When agency inspectors visited Massengill's plant in Bristol, he said, chemist Watkins
seemed unaware of the deaths associated with the company's new drug and aloof to the
problems the elixir had caused.

FDA demanded that Massengill send a second, more strongly worded recall telegraph
notice that warned that Elixir Sulfanilamide "may be dangerous to life."

After FDA's inspection of Massengill's manufacturing facility, the drug maker's attorney,
who was owner Sam Massengill's son-in-law, stated in Tulsa that the company had made
thorough and complete clinical tests before putting Elixir Sulfanilamide on the market,
and it was conducting further testing of the drug, according to the documentary film.

But FDA determined that there had been no clinical tests, and the agency found no
evidence that Massengill was conducting new tests with the drug.

However, federal inspectors had little legal authority to take action against Massengill.

Efforts to pass legislation that would strengthen FDA's regulatory authority had been
stalled in Congress for years, the documentary's narrator asserted in the one-hour film.

FDA investigators seized Massengill's elixir on a weak charge of misbranding, because

an elixir is supposed to contain alcohol and the company's product contained none.

On October 19, 1937, FDA undertook its largest operation at the time to collect every
bottle of the lethal elixir.

But patients who lived in remote parts of the South and beyond the reach of radio
bulletins that warned about the dangers of the drug, continued to take Elixir
Sulfanilamide as prescribed by their physicians.

An additional complication for FDA inspectors was the fact that some pharmacists sold
the drug without a prescription, the documentary stated.

Before all of the bottles of the drug were found, 107 people had died.

Sam Massengill was charged on more than 170 counts of misbranding. The court fined
him $26,000—the highest amount possible at the time.

An Oklahoma mother, whose daughter died nine days after taking Elixir Sulfanilamide,
wrote a letter to President Roosevelt about her daughter's death.
Davis said that "legend has it" that First Lady Eleanor Roosevelt read the letter.

"She could galvanize all sorts of support for an issue that she truly believed in," he said.

The letter was released to the media, and the "languishing" legislation that would give
FDA more authority received wide public support, Davis said.

Within six months of the Elixir Sulfanilamide tragedy, Congress passed the Food, Drug,
and Cosmetic Act of 1938, which requires FDA to certify the safety of new drugs before
they are put on the market.

"Elixir Sulfanilamide changed the way people look at medicines," said FDA's Swann.
"People are more aware, more conscious, more careful, and they also expect more from
the companies that provide pharmaceuticals. And they certainly expect to be protected by
the government."

Massengill's chemist, Harold Watkins, was later fired. He died of a self-inflicted gunshot
wound while cleaning his handgun. It is unknown whether he committed suicide or if the
death was an accident.

—Donna Young