In the annals of modern medicine, it was a horror story of international scope: thousands of babies dead in the womb and at least 10,000 others in 46 countries born with severe deformities. Some of the children were missing limbs. Others had arms and legs that resembled a seal’s flippers. In many cases, eyes, ears and other organs and tissues failed to develop properly.
The cause, scientists discovered by late 1961, was thalidomide, a drug that, during four years of commercial sales in countries from Germany to Australia, was marketed to pregnant women as a miracle cure for morning sickness and insomnia.
The tragedy was largely averted in the United States, with much credit due to Frances Oldham Kelsey, a medical officer at the Food and Drug Administration in Washington, who raised concerns about thalidomide before its effects were conclusively known. For a critical 19-month period, she fastidiously blocked its approval while drug company officials maligned her as a bureaucratic nitpicker.
Dr. Kelsey, a physician and pharmacologist later lauded as a heroine of the federal workforce, died Aug. 7 at her daughter’s home in London, Ontario. She was 101. Her daughter, Christine Kelsey, confirmed her death but did not cite a specific cause.
Dr. Kelsey did not single-handedly uncover thalidomide’s hazards. Clinical investigators and health authorities around the world played an important role, as did several of her FDA peers. But because of her tenacity and clinical training, she became the central figure in the thalidomide episode.
In July 1962, The Washington Post directed national attention on the matter — and on Dr. Kelsey — with a front-page article reporting that her “skepticism and stubbornness ... prevented what could have been an appalling American tragedy.”
The global thalidomide calamity precipitated legislation signed by President John F. Kennedy in October 1962 that substantially strengthened the FDA’s authority over drug testing.
The new regulations, still in force, required pharmaceutical companies to conduct phased clinical trials, obtain informed consent from participants in drug testing, and warn the FDA of adverse effects, and granted the FDA with important controls over prescription-drug advertising.
As the new federal law was being hammered out, Kennedy rushed to include Dr. Kelsey in a previously scheduled White House award ceremony honoring influential civil servants, including an architect of NASA’s manned spaceflight program.
“In a way, they tied her to the moonshot in showing what government scientists were capable of,” said Stephen Fried, a journalist who investigated the drug industry in the book “Bitter Pills.” “It was an act of incredible daring and bravery to say we need to wait longer before we expose the American people to this drug.”
Dr. Kelsey became, Fried said, “the most famous government regulator in American history.”
‘I was the newest person there and pretty green’
Dr. Kelsey had landed at the FDA in August 1960, one of seven full-time medical officers hired to review about 300 human drug applications per year.
The number of women pursuing careers in science was minuscule, but Dr. Kelsey had long been comfortable in male-dominated environments. Growing up in Canada, she spent part of her childhood in an otherwise all-boys private school. She had two daughters while shouldering the demands of medical school in the late 1940s.
In Washington, she joined a corps of reform-minded scientists who, although not yet empowered by the 1962 law that required affirmative FDA approval of any new drug, demanded strong evidence of effectiveness before giving their imprimatur.
At the time, a drug could go on the market 60 days after the manufacturer filed an application with the FDA. If the medical officer determined that the submission was incomplete, the drug company could provide additional information, and the clock would start anew.
Meanwhile, pharmaceutical drug companies commonly supplied doctors with new drugs and encouraged them to test the product on patients, an uncontrolled and dangerous practice that relied almost entirely on anecdotal evidence.
Thalidomide, which was widely marketed as a sedative as well as a treatment for pregnancy-related nausea during the first trimester of pregnancy, had proven wildly popular in Europe and a boon for its German manufacturer, Chemie Grünenthal.
By the fall of 1960, a Cincinnati-based drug company, William S. Merrell, had licensed the drug and began to distribute it under the trade name Kevadon to 1,200 U.S. doctors in advance of what executives anticipated would be its quick approval by the FDA.
The government later estimated that more than 2.5 million tablets were given to about 20,000 patients, several hundred of whom were pregnant.
The Merrell application landed on Dr. Kelsey’s desk within weeks of her arrival at the agency. “I was the newest person there and pretty green,” she later said in an FDA oral history, “so my supervisors decided, ‘Well, this is a very easy one. There will be no problems with sleeping pills.’ ”
Immediately the application alarmed her. Despite what she called the company’s “quite fulsome” claims, the absorption and toxicity studies were so incomplete as to be almost meaningless.
Dr. Kelsey rejected the application numerous times and requested more data. Merrell representatives, who had large potential profits riding on the application, began to complain to her bosses and show up at her office, with respected clinical investigators in tow, to protest the hold-up.
Dr. Kelsey’s FDA superiors backed her as she conducted her research. By February 1961, she had found more evidence to support her suspicions, including a letter in the British Medical Journal by an English doctor who reported that his patients on thalidomide experienced a painful “tingling” in the arms and feet.
Dr. Kelsey also discovered that, despite warnings of side effects printed on British and German drug labels, Merrell had not notified the FDA of any adverse reactions.
Another reason for her concern was that the company had apparently done no studies on pregnant animals. At the time, a prevailing view among doctors held that the placental barrier protected the fetus from what Dr. Kelsey once called “the indiscretions of the mother,” such as abuse of alcohol, tobacco or illegal drugs. Earlier in her career, however, she had investigated the ways in which drugs did in fact pass through the placenta from mother to baby.
While Dr. Kelsey stood her ground on Kevadon, infant deaths and deformities were occurring at an alarming rate in places where thalidomide had been sold. The development of seal-like flippers, a condition known as phocomelia that previously affected an estimated 1 in 4 million infants, began to crop up by the dozens in many countries.
Clinical investigators, because of a variety of complications including spotty tracking systems, only belatedly made the link to thalidomide.
Grünenthal began pulling the drug from the market in Germany in late 1961. Health authorities in other countries issued warnings. Merrell waited until March 1962 to withdraw its U.S. application. By then, at least 17 babies were born in the United States with thalidomide-related defects, according to the FDA.
Influence beyond thalidomide
Dr. Kelsey might have remained an anonymous bureaucrat if not for the front-page story in The Post. The newspaper had received a tip about her from staffers working for Sen. Estes Kefauver, a Tennessee Democrat who had been stalled in his years-long battle with the pharmaceutical industry to bolster the country’s drug laws.
The coverage of Dr. Kelsey gave her — and Kefauver — a lift. As thousands of grateful letters flowed in to Dr. Kelsey from the public, the proposed legislation became hard to ignore or to water down. The new law was widely known as the Kefauver-Harris Amendments.
“She had a huge effect on the regulations adopted in the 1960s to help create the modern clinical trial system,” said Daniel Carpenter, a professor of government at Harvard University and the author of “Reputation and Power,” a definitive history of the FDA. “She may have had a bigger effect after thalidomide than before.”
In 1963, Dr. Kelsey was named chief of the FDA’s investigational drug branch. Four years later, she was named director of the new Office of Scientific Investigations, a position she held until 1995.
She spent another decade, until her retirement at 90, working at the FDA’s Center for Drug Evaluation and Research. In that role, she advised the director of its compliance office on scientific and medical issues and analyzed historical drug review issues.
According to historians of the FDA, she was instrumental in establishing the institutional review boards — a cornerstone of modern clinical drug development — that were created after abusive drug testing trials were exposed in prisons, hospitals and nursing homes.
For decades, Dr. Kelsey played a critical role at the agency in enforcing federal regulations for drug development — protocols that were credited with forcing more rigorous standards around the world.
Name mistaken for a man’s
Frances Kathleen Oldham was born near Cobble Hill, on Vancouver Island, British Columbia, on July 24, 1914. Her father was a retired British army officer, and her mother came from a prosperous Scottish family.
The young “Frankie,” as she was called, grew up exploring the woods and shorelines, sometimes bringing home frogs for dissection. At McGill University in Montreal, she studied pharmacology — the effects of drugs on people — and received a bachelor’s degree in 1934 and a master’s degree in 1935.
A McGill professor urged her to apply for a research assistant job at the University of Chicago, where pharmacology professor Eugene Geiling accepted her without an interview. Geiling, who had mistaken the names Frances for the masculine Francis, addressed her by mail as “Mr. Oldham.”
“When a woman took a job in those days, she was made to feel as if she was depriving a man of the ability to support his wife and child,” Dr. Kelsey told the New York Times in 2010. “But my professor said: ‘Don’t be stupid. Accept the job, sign your name and put “Miss” in brackets afterward.’ ”
In Chicago, she helped Geiling investigate the 107 deaths that occurred nationwide in 1937 from the newly marketed liquid form of sulfanilamide, a synthetic antibacterial drug used to treat streptococcal infections. In tablet form, it had been heralded as a wonder-drug of the age, but it tasted unpleasant.
Because the drug was not soluble in water or alcohol, the chief chemist of its manufacturer, S.E. Massengill Co. of Bristol, Tenn., dissolved the sulfanilamide with an industrial substance that was a chemical relative of antifreeze. He then added cherry flavoring and pink coloring to remedy the taste and appearance.
Massengill rushed the new elixir to market without adequately testing its safety. Many who took the medicine — including a high number of children — suffered an agonizing death.
At the time, the FDA’s chief mandate, stemming from an obsolete 1906 law, was food safety. At the agency’s request, Geiling joined the Elixir Sulfanilamide investigation and put Dr. Kelsey to work on animal testing of the drug. She recalled observing rats as they “shriveled up and died.”
Amid national outrage over Elixir Sulfanilamide, Congress passed the Federal Food, Drug and Cosmetic Act of 1938, legislation that vastly expanded federal regulatory oversight over drugs and set a new benchmark for drug safety before marketing.
Massengill’s owner ultimately was fined a maximum penalty of $26,000 for mislabeling and misbranding; by technical definition, an elixir contains alcohol.
‘We need to take precautions’
Dr. Kelsey received a doctorate from Chicago in 1938, then joined the faculty. In 1943, she wed a pharmacology colleague, Fremont Ellis Kelsey.
After graduating from Chicago’s medical school in 1950, Frances Kelsey taught pharmacology at the University of South Dakota medical school and was a fill-in doctor at practices throughout the state. She also became a U.S. citizen before arriving in Washington in 1960 when her husband was hired by the National Institutes of Health. He died in 1966 after a heart attack.
Survivors include their daughters, Susan Duffield of Shelton, Wash., and Christine Kelsey of London, Ontario; a sister; and two grandchildren. Dr. Kelsey moved to Ontario from suburban Maryland in 2014.
Babies who suffered from the effects of thalidomide and survived grew up with a range of impairment. Some required lifelong home care. Others held jobs and were not severely hindered by their disabilities. Many legal settlements were reached between drug companies and the victims of thalidomide, and new claims continue to surface. Grünenthal formally apologized to victims of thalidomide in 2012.
The drug, however, never disappeared entirely. Researchers have investigated thalidomide’s effects on H.I.V. and Crohn’s disease and have conducted clinical trials for on its use for rheumatoid arthritis and macular degeneration, a leading cause of blindness.
In 1998, the FDA approved the drug for the treatment of lesions from leprosy. In 2006, thalidomide was cleared for use with the medicine dexamethasone for certain cases of multiple myeloma, a cancer of the bone marrow.
The agency enforced strict safeguards, including pregnancy testing, for such new uses. “We need to take precautions,” Dr. Kelsey told an interviewer in 2001, “because people forget very soon.”