Frances Oldham Kelsey

Frances Kathleen Oldham Kelsey Template:Post-nominals (Template:Nee Oldham; July 24, 1914 – August 7, 2015) was a Canadian-American<ref name="nyt-2015"/> pharmacologist and physician. As a reviewer for the U.S. Food and Drug Administration (FDA), she refused to authorize thalidomide for market because she had concerns about the lack of evidence regarding the drug's safety.<ref name="globe2014"/> Her concerns proved to be justified when it was shown that thalidomide caused serious birth defects. Kelsey's career intersected with the passage of laws strengthening FDA oversight of pharmaceuticals. Kelsey was the second woman to receive the President's Award for Distinguished Federal Civilian Service, awarded to her by John F. Kennedy in 1962.

Birth and education

Born in Cobble Hill, British Columbia,<ref name="heirloom"/> Kelsey attended St. Margaret's School in the provincial capital, graduating at age 15.<ref name="education">Kelsey attended Leinster Preparatory School, an all boys school, for a few terms before transferring to St. George’s School for Girls and then followed the headmistress to St. Margaret's School when St. George's was closed, ({{#invoke:citation/CS1|citation |CitationClass=web }}) Summarizing an article in the Times Colonist, October 16, 1962.</ref><ref name="fda1"/> From 1930 to 1931, she attended Victoria College (now University of Victoria). She then enrolled at McGill University, where she received both a B.Sc. (1934) and an M.Sc. (1935) in pharmacology.<ref name="heirloom" /> Encouraged by one of her professors, she "wrote to EMK Geiling, M.D., a noted researcher [who] was starting up a new pharmacology department at the University of Chicago, asking for a position doing graduate work".<ref name="fda1" /> Geiling, unaware of spelling conventions with respect to Francis and Frances, presumed that Frances was a man and offered her the position, which she accepted, starting work in 1936.<ref name="name confusion"/><ref>Template:Cite book</ref>

During Kelsey's second year, Geiling was retained by the FDA to research unusual deaths related to elixir sulfanilamide, a sulfonamide medicine. Kelsey assisted on this research project, which showed that the 107 deaths were caused by the use of diethylene glycol as a solvent. At that time, there was no law available to prosecute those who sold poison as medicine, and Kelsey observed the need to work around incomplete regulation.<ref name="sch">Template:Cite journal</ref> The next year, the United States Congress passed the Federal Food, Drug, and Cosmetic Act of 1938.<ref name="fda1" /> That same year she completed her studies and received a Ph.D. in pharmacology at the University of Chicago.<ref name="fda1" /> Working with Geiling led to her interest in teratogens, drugs that cause congenital malformations (birth defects).<ref name="nih1"/> She learned about the mechanism by which birth defects occur.<ref name="sch"/>

Academic career

Black-and-white photo of Kelsey standing beside a table laden with files; grasping eyeglasses and an open book, she looks to the camera and seems about to speak

Kelsey in the 1960s

Upon completing her Ph.D., Oldham joined the University of Chicago faculty. In 1942, like many other pharmacologists, Oldham was looking for a synthetic cure for malaria. As a result of these studies, Oldham learned that some drugs are able to pass through the placental barrier.<ref name="JH mag" /> During her work, she also met fellow faculty member Fremont Ellis Kelsey, whom she married in 1943.<ref name="fda1" />

While on the faculty at the University of Chicago, Kelsey was awarded her M.D. in 1950.<ref name="fda1" /> She supplemented her teaching with work as an editorial associate for the American Medical Association Journal for two years. Kelsey left the University of Chicago in 1954, decided to take a position teaching pharmacology at the University of South Dakota, and moved with her husband and two daughters to Vermillion, South Dakota, where she taught until 1957.<ref name="heirloom" />

She became a dual citizen of Canada and the United States in the 1950s in order to continue practicing medicine in the U.S., but retained strong ties to Canada where she continued to visit her siblings regularly until late in life.<ref name="globe2014"/>

Work on thalidomide

Black-and-white photo of a smiling Kelsey meeting with President John F. Kennedy; the medal for the President's Award for Distinguished Federal Civilian Service hangs around Kelsey's neck

Kelsey received the President's Award for Distinguished Federal Civilian Service from President John F. Kennedy, 1962

In 1960, Kelsey was hired by the FDA in Washington, D.C. At that time, she "was one of only seven full-time and four young part-time physicians reviewing drugs"<ref name="fda1" /> for the FDA. One of her first assignments at the FDA was to review an application by Richardson-Merrell for the drug thalidomide (under the tradename Kevadon) as a tranquilizer and painkiller with specific indications to prescribe the drug to pregnant women for morning sickness. Although it had been previously approved in Canada and more than 20 European and African countries,<ref name="acs"/> she withheld approval for the drug and requested to see clinical trial information.<ref name="heirloom" /> At the time, the FDA could only withhold approval for 60 days at a time, so she continually requested further information from the company every 60 days for over a year. Her initial reason for doing this was that the testimonials supplied by Richardson-Merrell contained no scientific methodology, and she recognized their authors as having published suspicious articles in the past.<ref>Template:Cite news</ref><ref name="sch"/> Kelsey also observed that the application said nothing about the chirality of thalidomide.<ref name="vbs">Template:Cite book</ref>

In December 1960, Leslie Florence published a letter in the British Medical Journal connecting thalidomide to neurological symptoms. Kelsey saw this letter and added Florence's observed symptoms to her ongoing data requests.<ref name="fda1" /><ref name=":0">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> The unexpected neurological effects caused her to recall her earlier work on the mechanism of birth defects, so she also requested animal studies to demonstrate that the drug would not be harmful to the fetus.<ref name="sch"/><ref name=":0" /> In fact, Richardson-Merrell had reportedly discovered birth defects when the drug was tested on rats but did not report this finding; Kelsey was instead sent misleading partial data suggesting the product was safe for pregnant women. Despite the fact that thalidomide was already widely used in Europe and elsewhere, Kelsey remained suspicious and scrutinized this data with concern and skepticism, sometimes asking her husband to check her conclusions.<ref>Template:Cite book</ref> As 1960 turned to 1961, Kelsey's continual requests for more information incurred the ire of her contact at Richardson-Merrell, who insisted on speeding up the approval process and attempted to escalate the application, but Kelsey's superiors at the FDA stood by her.<ref name="sch"/>

Kelsey's insistence that the drug should be fully tested prior to approval was vindicated in November 1961 when the births of deformed infants in Europe were linked to thalidomide ingestion by their mothers during pregnancy.<ref name="fda3"/><ref name="fda4"/> Researchers discovered that the thalidomide crossed the placental barrier and caused serious birth defects.<ref name="JH mag" /> In March 1962, after distributing "experimental" tablets to tens of thousands of patients without approval (with 17 malformed births confirmed and dozens more suspected<ref name="vbs"/>), Richardson-Merrell at last withdrew their FDA application.<ref name="smith">Template:Cite news</ref> Kelsey was hailed on the front page of The Washington Post as a heroine<ref name="post"/> for averting a large-scale tragedy in the U.S.<ref name="nih2"/> Morton Mintz, author of The Washington Post article, said Template:Nowrap prevented ... the birth of hundreds or indeed thousands of armless and legless children."<ref name="post" /> Kelsey insisted that her assistants, Oyama Jiro and Lee Geismar, as well as her FDA superiors who backed her strong stance, deserved credit as well. The narrative of Kelsey's persistence was used to help pass rigorous drug approval regulation in 1962.<ref name="nyt-2015"/>

After Mintz broke the story in July 1962, there was a substantial public outcry. The Kefauver Harris Amendment was passed unanimously by Congress in October 1962 to strengthen drug regulation.<ref name="fda3" /><ref name="fda4"/> Companies were required to demonstrate the efficacy of new drugs, report adverse reactions to the FDA, and request consent from patients participating in clinical studies.<ref name="CHFArticle">Template:Citation</ref> The drug testing reforms required "stricter limits on the testing and distribution of new drugs"<ref name="JH mag" /> to avoid similar problems. The amendments, for the first time, also recognized that "effectiveness [should be] required to be established prior to marketing."<ref name="fda3" /><ref name="fda4"/>

As a result of her blocking American approval of thalidomide, Kelsey was awarded the President's Award for Distinguished Federal Civilian Service by John F. Kennedy on August 7, 1962,<ref name="jfk"/> becoming the second woman so honoured.<ref name="nwhf"/> After receiving the award, Kelsey continued her work at the FDA. There, she played a key role in shaping and enforcing the 1962 amendments.<ref name="nih2" /> She was named Director of the Investigational Drug Branch.<ref name="heirloom" />

Further FDA career

In 1966, Lyndon B. Johnson appointed James L. Goddard as Commissioner of Food and Drugs. Goddard resented the public attention Kelsey continued to receive and believed widespread rumors spread by pharmaceutical industry executives that Kelsey had delayed the thalidomide application through pure laziness. This was precisely the opposite of the truth: most applications were automatically approved by reviewers ignoring the 60 day deadline, while Kelsey had carefully sent out data requests for over a year. Regardless, Kelsey was demoted from Director of the Investigational Drug Branch to Chief of the Division of Oncology and Radiopharmaceutical Drug Products, where she was given little work.<ref>Template:Cite book</ref>

After Goddard's departure, Kelsey was again appointed Director of Scientific Investigations, and continued in this position for many decades. She was involved in the contentious regulation of diethylstilbestrol, which also caused birth defects, and dimethyl sulfoxide. In 1994, the Frances Kelsey Secondary School in Mill Bay, British Columbia, was named in her honour.<ref name="schoolnamed"/> She attended the opening ceremony despite having suffered broken ribs and a vertebral compression fracture on the way to the ceremony. In 1995, when she was eighty-one, the FDA's Center for Drug Evaluation and Research created a special position for her, Deputy for Scientific and Medical Affairs in the Office of Compliance.<ref>Template:Cite book</ref>

Later life and death

Informal colour photo of Kelsey in three-quarter profile

Kelsey (age 87) at the FDA reception commemorating her induction into the National Women's Hall of Fame

Kelsey retired from the FDA in 2005, at age 90, after 45 years of service.<ref name="acs" /> In 2010, the FDA presented Kelsey with the first Drug Safety Excellence Award and named the award after her,<ref name="nyt-2010"/><ref name="post-2010">Template:Citation.</ref> announcing that it would be given to one FDA staff member annually.<ref name="FDA-award"/> In announcing the awards, Center Director Steven K. Galson said: "I am very pleased to have established the Dr. Frances O. Kelsey Drug Safety Excellence Award and to recognize the first recipients for their outstanding accomplishments in this important aspect of drug regulation."<ref name="fda2005"/>

Kelsey turned 100 in July 2014,<ref name="Centenary"/> and shortly thereafter, in the fall of 2014, she moved from Washington, D.C., to live with her daughter in London, Ontario.<ref name="G&M-2015-07-01"/> In June 2015, when she was named to the Order of Canada, Mercédes Benegbi, a thalidomide victim and the head of the Thalidomide Victims Association of Canada, praised Kelsey for showing strength and courage by refusing to bend to pressure from drug company officials, and said "To us, she was always our heroine, even if what she did was in another country."<ref name="G&M-2015-07-01"/>

Kelsey died in London, Ontario, on August 7, 2015, at the age of 101,<ref name="post-2015"/> less than 24 hours after Ontario's Lieutenant-Governor, Elizabeth Dowdeswell, visited her home to present her with the insignia of Member of the Order of Canada.<ref name="G&M-2015-08-07"/>

Legacy and awards

• 1962 – President's Award for Distinguished Federal Civilian Service<ref name="acs" />
• 1963 – Gold Key Award from University of Chicago, Medical and Biological Sciences Alumni Association<ref name="goldkey"/>
• 1994 – Chosen as the namesake for Frances Kelsey Secondary School which opened in 1995.
• 2000 – Inducted into the National Women's Hall of Fame<ref name="nwhf" />
• 2001 – Named a Virtual Mentor for the American Medical Association<ref name="ama"/>
• 2006 – Foremother Award from the National Center for Health Research<ref>{{#invoke:citation/CS1|citation

|CitationClass=web }}</ref>

• 2010 – Recipient of the first Dr. Frances O. Kelsey Award for Excellence and Courage in Protecting Public Health given out by the FDA<ref>Template:Cite news</ref>
• 2012 – Honorary doctor of science degree from Vancouver Island University<ref name="VIU"/>
• 2015 – Named to the Order of Canada<ref name="G&M-2015-07-01"/>

See also

• European Medicines Agency

Further reading

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Biographies

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