Frances Oldham Kelsey, the FDA, and the Battle against Thalidomide
In the early 1960s, Dr. Frances Oldham Kelsey of the U.S. Food and Drug Administration became one of the most celebrated women in America when she prevented a deadly sedative from entering the U.S. market. A Canadian-born pharmacologist and physician, Kelsey saved countless Americans from the devastating side effects of thalidomide, a drug routinely given to pregnant women to prevent morning sickness.
In this excerpt from Frances Oldham Kelsey, the FDA and the Battle against Thalidomide, Cheryl Krasnick Warsh looks at how Kelsey and the team of scientists she worked with prevented the sale of Thalidomide in the US.
Frances Kelsey and her team did not know how toxic thalidomide was in December 1960. At that time, the onus was on the FDA to reject or delay a NDA within sixty days of receipt, or it would be automatically approved for market. If there were no objections, or if the staff missed the deadline through oversight (which had happened once), the drug would be approved.
The thalidomide application was reviewed by three experts. Kelsey reviewed the clinical (human) reports; that is, she looked over the reports submitted by the company or the investigators hired by the company to perform the clinical trials. She determined whether the trials were random, double- blind studies with a significant number of participants, rather than a list of testimonials, such as “I prescribed this drug to two patients and their condition miraculously disappeared. I even used it on myself.” She also judged whether negative side-effects were faithfully reported in detail. She red-flagged the side-effects, related them to other compounds used for similar conditions (such as other sedatives), and determined if the findings warranted the conclusions made by the researchers and the company in the NDA.
The other experts comprised an immigrant who found wartime America to be a safe haven, and an American who found his homeland to be anything but safe.
The chemistry studies were analyzed by Lee Geismar, whose Jewish family fled from Germany in 1938 to England, where she attended boarding school, and then immigrated to New York in 1940 under a cousin’s sponsorship. Geismar originally wanted to be a fashion designer, but she went the practical route and studied chemistry and physics at Hunter College, where she took the civil service examination with the rest of her classmates. She worked in a hospital until she received a telegram offering her an interview with the government on the basis of her exam scores, and she joined the FDA in 1947.
The animal studies were reviewed by Dr. Jiro Oyama, a Nisei (Japanese American) whose family underwent the trauma of forced relocation to prison camps in California and Arkansas after Pearl Harbor. Upon the insistence of his older sister, Oyama answered yes on the two most controversial questions on the infamous War Relocation Agency’s loyalty questionnaire for Nisei, affirming that he would serve in combat against Japan, and foreswear any prior allegiance to the Japanese emperor, which granted him security clearance for future employment.…Oyama’s family were released from the Arkansas camp in 1944, and he enrolled in the University of Cincinnati, but was soon drafted. After Hiroshima, he was sent to Japan to serve as an army interpreter… Back in the US, he attended Northwestern and George Washington universities. He obtained employment at the NIH, the FDA, and finally at NASA Ames.
When Frances Kelsey delayed approval of Richardson-Merrell’s Kevadon NDA, potentially thousands of American babies were saved from the fate of their less fortunate counterparts in Europe and elsewhere in the world. An estimated 100,000 newborns were affected by thalidomide globally, suffering from neurological disorders, cardiac issues, or other serious birth defects, with approximately ten thousand of them born phocomeliac (i.e., with deformed extremities).¹ These latter became known as thalidomide babies, a term which resonated with horror and pity in the 1960s.
Kelsey’s actions were validated weeks later, when an eyewitness to the European tragedy personally shared her experiences with the FDA medical review team. This was Dr. Helen Taussig, one of the greatest medical scientists of the twentieth century.¹ Taussig, dyslexic and hearing impaired, was a brilliant researcher and clinician, and the founder of the specialty of pediatric cardiology.
Kelsey’s actions were validated weeks later, when an eyewitness to the European tragedy personally shared her experiences with the FDA medical review team.
In early 1962, Taussig was nearing retirement as head of the Children’s Heart Clinic at Johns Hopkins University Hospital. She received letters from European physicians encountering a spike in newborns with heart defects who also were born phocomeliac. A German pediatrician who had trained with her urged Taussig to come to Europe and see for herself.…
Taussig was so shaken by the enormity of the tragedy that upon her return to the United States, she immediately submitted a report for publication in several leading medical journals. She arranged meetings with national medical associations, considering it imperative to get the information across to as many physicians, hospitals, and public health agencies as possible, that there was a new drug available internationally that could be lethal to newborns. In her reports, she also stressed that all new drugs must undergo exhaustive tests before they were released on the consumer market, so that future medical tragedies could be averted.³
Taussig then contacted her former pupil, FDA’s Dr. John Nestor, who along with Kelsey, Irwin Siegel, and Irvin Kerlan would be characterized in the press as “young Turks” who advocated professionalism and science over politics and negotiation in the drug review process… On April 6, 1962, Taussig invited Nestor and Kelsey to her Baltimore home, and Kelsey was very impressed to meet one of her heroines. Taussig’s report to them was enlightening, albeit not in a good way.
[It had been previously] reported to Kelsey that the association between the drug and the malformations was not wholly established, given that thalidomide had been used for several years in Europe with no apparent difficulties. Taussig countered that this was simply not true, and she detailed the findings of her European trip. To put the situation into perspective, Taussig noted that in her whole medical career, she had seen only two cases of congenitally missing limbs. Many of the physicians she visited had fifty or sixty such patients in the previous three years. About one-third of those babies did not survive. Taussig also clarified that the dangerous period to the fetus was between the thirtieth to the sixtieth day after the last menstrual period and that as little as one pill could do the damage. Many affected women might not have known that they were pregnant at this point.
Taussig noted that in her whole medical career, she had seen only two cases of congenitally missing limbs. Many of the physicians she visited had fifty or sixty such patients in the previous three years.
Taussig also confirmed that the original Grünenthal pharmacological reports submitted by Merrell had been altered or incomplete; her European contacts had stated that the early studies on thalidomide had found fetal malformations in rabbits. She emphasized to Kelsey and Nestor, therefore, that it was essential to test all drugs on pregnant animals before they were approved for market. Contrary to widespread belief in medical communities at this time, the thalidomide experiences confirmed that drugs could indeed pass through the placenta from mother to fetus. Taussig was impressed by Kelsey, and the two female physicians remained life long friends. Taussig would write to “Dear Frances,” but Kelsey always replied to “Dr. Taussig.”
Kelsey left the meeting with Taussig fully resolved that her meticulous approach to the thalidomide application had been vindicated. On April 11, she sent an NDA letter to the Merrell subsidiary National Drug Company, which distributed Contergan. In her letter, Kelsey wanted to know whether Contergan was still in investigational use, and what the company had done to warn physicians of its toxic properties. She also queried whether measures had been taken to inform physicians of the association of fetal defects and maternal ingestion of the drug during pregnancy, when that association became known to the company. Finally, Kelsey demanded a complete and up-to-date list of all physicians who had been supplied thalidomide for investigational use.⁴
Her team’s battle to save America’s babies from the deadly sedative became active combat, as FDA inspectors fanned out to collect existing samples and obtain the names of potential victims from medical personnel. This is why Kelsey joined the FDA — the protective work was personally gratifying. Yet Taussig was not quite finished with her printed remarks. The next article she wrote on thalidomide was the catalyst for major reforms to drug regulations. It also highlighted the role played by Kelsey, which was received with the gratitude of a national and international public.
¹ This estimate was provided by the British organization, The Thalidomide Trust, https://www.thalidomidetrust.org/
² Frances Oldham Kelsey, 1967, “An Assembly talk at the National Cathedral School,” January 31. Private Collection. SD, Shelton, WA.
³ Memo of Conference, Taussig, Kelsey, Nestor.
⁴ “Chronology of Transactions with William S. Merrell and National Drug Company regarding Kevadon/ Contergan (Thalidomide).” Memo, John Archer, MD, Bureau of Medicine, to George P. Larrick, Commissioner and Winton B. Rankin, Assistant Commissioner, FDA, April 18, 1962. Re: Contergan (NDA- 12711). LOC. KP. Part II: Subject File, 1902– 2012, Box II: 201, “Kevadon- Memoranda, 1960– 1962,” 3.
Cheryl Krasnick Warsh is Professor of History at Vancouver Island University in Nanaimo, Canada. Dr. Warsh has published books on the history of asylums, women’s health, children’s health, consumerism, and alcohol and drug use. She served as long-term editor-in-chief of the Canadian Bulletin of Medical History and was co-editor of Gender & History. Dr. Warsh was a Fulbright Fellow, AMS/Hannah Fellow, and the inaugural recipient of the Vancouver Island University Distinguished Researcher Award. In 2017, she was elected a Fellow of the Royal Society of Canada for her contributions to Canadian medical history.
