In September of 1960, the American pharmaceutical company Richardson-Merrell submitted their application to the FDA for the approval of Europe’s new wonder drug, thalidomide, to be introduced to the American market. In Germany and England, the drug had been heavily prescribed to help anxiety, sleeplessness, and morning sickness, and was widely touted for its apparently complete lack of toxicity, and Merrell had reason to believe that its application was a mere formality on the way to untold profits.
And so it might have been, had their application landed on the desk of an individual slightly less discerning than Frances O. Kelsey, a relatively new FDA official who would not be bullied into ignoring the disturbing gaps in Merrell’s application. Why, for a drug that was being so readily prescribed for morning sickness, were there no studies on its effects on pregnant women? Why were reports about irreversible numbness in the extremities among the drug’s more regular users being sloughed off as statistically unimportant? What might a drug that had an effect on an adult nervous system do to a body just beginning to develop? These were questions to which Kelsey demanded answers, and while Merrell did everything it could to obfuscate and go over her head, medical investigators gathered the evidence to conclusively demonstrate what thalidomide could do to a developing fetus, and what it might have done to hundreds of thousands of American babies had Kelsey not stood her ground.
Frances Kathleen Oldham was born July 24, 1914, on Vancouver Island to a Scottish mother and an Australian father who was a soldier in the British Royal Field Artillery. As a girl she attended Leinster Preparatory School where she was for some time the only girl in a sea of boys. She received top grades in her elementary and middle schools, but was often written up by her teachers for poor conduct and a tendency to disobey the rules. She graduated at the age of fifteen (this was when high school only lasted three years, but her start at a gradeless school that allowed you to work at the level of your ability instead of the grade level arbitrarily set by your age also gave her a good start) and made her way to Victoria College to start her studies in biology, a topic hardly covered in her high school curriculum.
Oldham’s senior year introduced her to classes in biochemistry and pharmacology, which set her mind thinking along the lines of body-drug interactions which would lie at the center of her later work at the FDA. In 1934, she graduated from McGill University (where she had transferred after two years at Victoria), took a look around at the world as it was in 1934, in the depths of the Great Depression, and made the entirely wise decision to turn right back around and enter a graduate program instead of throwing herself into the churning hostility of the 1930s private sector. She worked for a couple of years with Raymond Stehle, studying the posterior lobe of the pituitary, which was at the time considered to be the decided lesser of the two pituitary lobes, but which Stehle and Oldham’s work helped to revive interest in (today, by the by, the posterior is recognized as a superstar, playing an important role in oxytocin and vasopressin secretion).
Oldham’s work on the posterior pituitary earned her a Master’s Thesis in pharmacology in 1935, but 1935 was hardly any better a year to enter the workforce than 1934 was, and so Oldham went on the hunt for a new institution where she could develop her academic skills while receiving just enough money to live as she waited out the hard economic times. She wrote to Eugene Geiling at the University of Chicago, where she was told a pharmacology opening existed. Geiling was another posterior pituitary booster, and when he received Oldham’s note he immediately wrote back offering her a position.
Or rather, he wrote back offering him a position, as Geiling was under the impression that Frances Oldham was the name of a man. Oldham accepted the position, making clear in her letter that she was in fact a woman, and proceeded to the University of Chicago, where she became Geiling’s first PhD student. Here, in 1937, she had her first experience with the pharmaceutical industry’s tragic tendency to rush products onto the shelves. Sulfanilamide was one of the truly great drugs of the Twentieth Century – produced by IG Farben in 1932 from a red dye, sulfanilamide seemed to be able to bind with bacteria in a way that offered a path out of the horrendous fatalities humanity regularly suffered at the hands of minor infections throughout our history.
It was the drug that kicked off a new era of antibiotics and that saved more lives than it is possible to reckon, but it was also not particularly pleasant to take. The pills were big, tasted bad, and often caused upset stomach and bowels – drawbacks that were decidedly better than dying at the age of 23 from a staph infection, but that pharmaceutical companies were eager to find a workaround for in the form of a liquid preparation of the drug. S.E. Massengill Company managed to do just that in 1937 by dissolving sulfanilamide in diethylene glycol.
Diethylene glycol is a great solvent, it will dissolve all sorts of stuff. But it’s also a close cousin to ethylene glycol, which we know as the primary component in antifreeze, and has a similar, if lesser, toxicity. Massengill did not know this and did not bother to perform the clinical studies needed to establish it as they rushed to get their liquid sulfanilamide on the market.
The result was dozens of grizzly deaths which the FDA did not have the facilities to investigate. So, they turned to Geiling and Oldham to do the toxicity studies that Massengill should have done in the first place. Together, they determined that diethylene glycol causes kidney failure (today we believe this is likely because of acidosis caused by diethylene glycol’s breakdown into the weak acid HEAA, which is partially reabsorbed and throws off the kidney’s normal acid regulation mechanisms). This was an important result which proved the value of animal testing before the release of new pharmaceutical products, and lead directly to the 1938 Federal Food, Drug, and Cosmetic Act, which substantially expanded the powers of the FDA and required its pre-approval of new medical devices and substances before their public release.
Just as that act was passing Congress, Oldham received her PhD in pharmacology, and elected to stay on at the University of Chicago until she married Ellis Kelsey, a fellow Chicago instructor, in 1943. University rules stated that two individuals from the same family could not have a job in the same department, and so it was decided that Ellis would remain in his position while Frances returned to medical school to get her MD, which she earned in 1950. With yet another degree fresh in her pocket, she decided to take a job at The Journal of the American Medical Association, which was attempting to increase its number of articles on new developments in medication. Kelsey’s job was to wade through new drug papers to find ones worth publishing, where she gained a crucial insight that would support her in her later struggle over thalidomide, namely the realization that many pharmaceutical companies were grotesquely slapdash not only in their methodology, but in their reporting of results, neglecting to do key tests, understating potential side effects, and overstating their products’ general safety.
Kelsey was in this position from 1952 to 1954, when Ellis was offered a job in South Dakota that necessitated moving the family (Frances had had two daughters by that time, one born in 1947 and the other in 1949). In 1960, Kelsey was hired by the FDA as one of seven full time researchers evaluating the safety of new pharmaceutical products. SEVEN. Fewer people than are required to side a full baseball time, and yet they were responsible for rigorously monitoring an entire nation’s drug system (today the FDA has around 11,000 employees, by contrast). Her first day was August 1, 1960, and within a month the application for thalidomide made its way to her desk.
At the time, the drug, which originated with the German pharmaceutical company Chemie Grunenthal, had been easily and seamlessly approved for use in multiple European countries and Canada, and the drug’s US distributor, Merrell, expected similar celerity for its application. Reading through their submitted documents, however, Kelsey noted many of the insufficiencies that she had come across during her time at the AMA – incomplete documentation, non-rigorous or simply non-existent clinical trials, and a disturbing tendency to shrug away some of the reports filtering in from Europe of a small percentage of thalidomide users experiencing peripheral neuritis. A potential impact on nerve function was a serious matter, and Kelsey reasoned that it might be a particularly serious problem for developing fetuses, which was one area of study that Merrell covered in only the most cursory of fashions.
She held up Merrell’s application for approval until more tests could be done. Meanwhile, doctors and journalists in Europe began noticing a strange uptick in the number of infants born with greatly shortened or in some cases entirely absent arms and legs, their feet and hands emerging more or less directly from their torsos, a condition known as phocomelia. It took a while for the culprit to be found because of the particular time sensitivity of thalidomide’s impact on fetal development. A woman taking a pill to ease morning sickness after the 42nd day of pregnancy by and large didn’t result in any developmental defects in her offspring, but so much as a single pill taken during the 20 to 42 day window could drastically impair peripheral or central development. The result was that a lot of women regularly took thalidomide but had no adverse effects as a result, because they didn’t take it during the critical window, while other women only ever took a couple of pills, but because of tragic timing, ended up with a malformed child.
Separating out the statistical complications caused by thalidomide’s time sensitivity took some doing and time, but fortunately Kelsey’s insistence on thorough documentation and relevant testing kept the drug from officially hitting the US market in 1960 or 1961, when the company was lobbying hard with Kelsey’s superiors to have her reservations overridden as the persnicketiness of an overwrought woman in over her head. Because of the era’s lax rules surrounding the distribution of samples to doctors, some thalidomide did find its way to the general US population, resulting in some 17 cases of thalidomide-related birth defects, but the scale of the tragedy was never allowed to reach the heights that were soon uncovered in Europe and Canada, where it is estimated 2000 children died and a further 10,000 bore lifelong limb-shortening birth defects due to maternal use of the drug.
By mid November 1961, Widukind Lenz in Germany and William McBride in Australia had compiled conclusive data that thalidomide caused birth defects if taken within a certain developmental window, and by November 30 Grunenthal reluctantly pulled the drug from the world market, though supplies of it continued to be available in some countries until 1963. It is estimated that Kelsey’s insistence on rigorous testing and documentation saved tens of thousands of children, and had an even longer impact by waking the country to persistent weaknesses in its new drug policies.
In October 1962, less than a year after the full extent of the thalidomide tragedy was revealed, the Kefauver-Harris Amendment overwhelmingly passed both houses of Congress and was signed into law by President Kennedy on October 10. The law, which amended the 1938 law which Kelsey’s work had brought into existence following the sulfanilamide deaths, required that doctors get informed consent from their patients before giving them trial drugs, that pharmaceutical companies publish side effect information on their products and report any knowledge of adverse effects to the FDA, and that all existing medications undergo sweeping re-evaluation to determine their actual efficacy.
Kelsey’s adopted country never forgot the service she had rendered it, honoring her many times over in the coming decades, from the President’s Award for Distinguished Federal Civilian Service in 1962 to the Foremother Award from the National Center for Health Research in 2006. And Kelsey, for her part, never let the fame go to her head but rather continued to dutifully play her part keeping medical companies honest and their products safe for decades after the thalidomide episode, not fully retiring until 2005, at the age of ninety. She died some ten years later, just two weeks after her 101st birthday, and one day after her native country awarded her with its second highest honor, the Order of Canada.
FURTHER READING: There is no shortage of books out there about the thalidomide tragedy. Suffer the Children (1979), Dark Remedy (2001), and The Thalidomide Catastrophe (2018) have all retold the tale for new generations, but the only book that focuses exclusively on Frances Kelsey is 2018’s Frankie: How One Woman Prevented a Pharmaceutical Disaster by James Essinger and Sandra Koutzenko. It has some structural problems and a marked tendency to pad and repeat the material, but the background on the development of the pharmaceutical industry in the early 20th century is well told.
Lead Photo Credit: By The U.S. Food and Drug Administration – President Kennedy & Frances O. Kelsey (FDA 172), Public Domain, via Wikimedia Commons