In one of the worst cases of corrupt medical science, a drug named thalidomide swept throughout the world, nearly matching aspirin in sales, and caused what was described as the “the worst man-made medical disaster ever.” In this devastating scandal, over 10,000 children were born with severe deformities including misshapen limbs and damage to internal organs due to the company’s corrupt research practices that omitted important tests and data, and continuous suppression of data that showed the dangers of thalidomide. 50 years after the scandal, the company, Grünenthal, released an apology to thalidomide victims after attempting to cover up for decades what was described as a ‘crime against humanity’. But as described by Harold Evans, a journalist who campaigned for the fair compensation of thalidomide victims, “Fifty years of injustice is not to be assuaged by the most heartfelt apology, unaccompanied as it is by any compensation for the pain and suffering thousands of survivors endure every day.”
The Beginnings of Thalidomide
In 1954, German pharmaceutical firm Chemie Grünenthal developed a sleeping drug that claimed to be so safe that the researchers “could not find a dose high enough to kill a rat.” An overdose of barbiturates, the sedative used at the time, would cause death, while an overdose of this new drug would only cause a deep sleep without the risk of drug addiction. This drug was used as a tranquilizer and a treatment for colds, flu, nausea, and even macular degeneration, diabetes, autoimmune diseases, and cancer. Because of its non-addictive properties and lack of toxicity at high doses, many people hailed thalidomide as a ‘wonder drug.’
However, the reason thalidomide is known today is because of its use in treating morning sickness in pregnant women. This was popularized when Australian obstetrician Dr. William McBride prescribed the off-label use of thalidomide for pregnant women, as he noticed the effects thalidomide had on relieving morning sickness. Off-label use, which refers to the unapproved use of an approved drug, is still a common and legal practice. This practice spread rapidly around the world, and doctors in 48 countries began prescribing thalidomide for pregnant women.
Thalidomide was sold under 37 brand names and 14 different companies, including under the trade names Contergen, Distaval, and Talidex. It was aggressively marketed to 46 countries, including in Japan, Australia, and Europe, with the guarantee that it was completely safe for pregnant women and unborn children. It could be bought over-the-counter, and by the 1960s, the sales of thalidomide nearly matched those of aspirin.
Thalidomide Caused Babies to be Born with Grotesque Birth Defects
By the 1950s and 1960s, thalidomide was widely used to treat nausea in pregnant women. However, physicians began noticing a link between mothers who took thalidomide and congenital defects in children. On December 25th, 1956, a child was born with severely deformed ears to a Chemie Grünenthal employee – the first thalidomide baby, but in the years following, there would be more than 10,000 thalidomide babies born. German pediatrician Dr. Widukind Lenz first came to the realization that thalidomide may be dangerous to fetuses in 1961 when he noticed that around 20% of deformed babies had mothers who had taken thalidomide during pregnancy. He presented his hypothesis that prenatal exposure to thalidomide caused severe birth defects to Chemie Grünenthal in November 1961. In Australia, Dr. William McBride, the doctor who first popularized the use of thalidomide, discovered that mothers who had taken thalidomide during pregnancy had babies with shortened or absent limbs, malformed hands and fingers, as well as damage to the eyes, ears, face, brain, internal organs, and skeletal structure. By the early 1960s, various papers in German medical journals began documenting the harmful effects of the long-term use of thalidomide, including nerve inflammation and damage.
How Were the Dangers of Thalidomide Not Detected During Testing?
This drug, known as thalidomide, has a chemical formula of C13H10N2O4. In order to assess the safety of the drug, Chemie Grünenthal conducted standard toxicity tests on mice which caused scientists to believe that the drug was safe even at very high doses. The company claimed that the scientists had done all possible tests on thalidomide to ensure the safety of the drug, including for pregnant women. However, reproductive tests were not conducted with thalidomide, even though other tranquilizer drugs conducted tests for teratogenic effects, which would have been able to show the harmful effects of thalidomide on fetuses. Dr. G. Edward Paget, director of Inveresk Research Institute stated about drug testing during the 1950s that, “Any ICI drug likely to be used by pregnant women would have certainly been tested for its effect on pregnant animals.”
In addition to the lack of reproductive tests, scientists at the University of Stockholm investigated the research data on thalidomide, and stated, “The number of animal experiments in the toxicity test were far too small; because of this a low frequency of side effects could not be detected, even though these are important for a sedative like thalidomide and very necessary if the substance is to be declared unpoisonous. The conventional toxicological and pharmacological tests are most unsatisfactory. Kunz, Keller and Mückter [scientists at Chemie Grünenthal] tried to hoodwink the reader by creating a false impression of the scope of their tests.”
Without proper drug testing and reports of toxicity, how did thalidomide stay on the market for so long? In one of the worst cases of corrupt medical science, it was discovered that Chemie Grünenthal actively attempted to suppress any evidence that thalidomide caused harm to patients. Dr. Widukund Lunz, one of the key players in the downfall of thalidomide, reported that he was threatened with legal action by Chemie Grünenthal for highlighting the link between thalidomide and birth deformities. A paper by Dr. Horst Frenkel, which showed that thalidomide was linked to 20 cases of nerve damage, was repeatedly delayed for publication when Chemie Grünenthal appealed to the medical journal’s editorial board to block these publications. The company also claims that reproductive tests were not commonly conducted at the time because scientists had not discovered that a drug was capable of reaching a fetus, but reproductive tests had been done on drugs used by pregnant women since 1944.
“Grünenthal acted in accordance with the state of scientific knowledge and all industry standards for testing new drugs that were relevant and acknowledged in the 1950s and 1960s.”Harald Stock, Chief Executive Officer of Grünenthal (formerly Chemie Grünenthal)
Dr. Frances Oldham Kelsey, the Woman Who Saved the United States from Thalidomide
In the wake of thalidomide’s aggressive global marketing, one woman, Dr. Frances Oldham Kelsey bravely faced pressures from the industry and regulatory bodies in order to prevent thalidomide from ever entering the market in the United States. Born in 1914 in Canada, Dr. Frances Oldham Kelsey pursued a degree in pharmacology from McGill University before pursuing her Ph.D. in pharmacology from the University of Chicago, during a time when women in science was rare. Her training in pharmacology would prove to be crucial to her decision to reject thalidomide in the United States. In August 1960, Dr. Kelsey had just landed a job at the Food and Drug Administration (FDA), where she was one of the seven medical officers reviewing 300 yearly applications for drug approval. During this time, a drug could go on market 60 days after the drug manufacturer filed for approval from the FDA. However, if a medical officer rejected the application, the manufacturer would have to provide additional information and repeat the process. In her first month on the job, Dr. Kelsey was assigned what the FDA thought would be an easy case – thalidomide, sold under the brand name Kevadon by the pharmaceutical company Richardson-Merrell. After all, it had already been approved and used extensively in Europe, so it was expected that this drug would easily receive approval by the FDA.
The main appeal of thalidomide was the safety of the drug, as it seemed like there were no toxic side effects even when taken in large quantities, unlike barbiturates which could induce death. However, in Dr. Kelsey’s postgraduate research at the University of Chicago in 1942, she had conducted research on quinine as a synthetic treatment for malaria, which was tested in rabbits. While adult rabbits could quickly metabolize quinine, in pregnant rabbits, the drug was able to pass through the placental barrier, where the fetus was unable to metabolize the drug at all. In their application for thalidomide, Dr. Kelsey noted that the toxicity and absorption studies were utterly incomplete with no research done on pregnant animals and no rigorous clinical trials. The manufacturer filed for approval again with additional information, but Dr. Kelsey again rejected the application because she stated that the evidence was “testimonial, not clinical, in nature.” By this time, it was nearing the holiday season, which is a lucrative time for sedative sales. Richardson-Merrell was impatient for FDA approval, as they had tons of Kevadon ready to sell and had already sent 1,000 Americans physicians thalidomide samples. Representatives from Richardson-Merrell began pressuring Dr. Kelsey by complaining to her bosses and showing up at her office, while also attempting to bypass her approval. She was described as a “fussy, stubborn, unreasonable bureaucrat” by Richardson-Merrell.
In February 1961, a letter published in the British Medical Journal further propelled Dr. Kelsey’s skepticism on the safety of thalidomide. In this letter, a British physician documented that patients who had taken thalidomide for long periods of time experienced a painful sensation in their arms and feet. In addition, Dr. Kelsey noticed that there were no adverse side effects listed on the FDA approval application, even though there were side effects listed on the British and German drug labels for thalidomide. These concerns were brought up to Richardson-Merrell, including the concern that thalidomide may be adversely affecting limbs in fetuses, but the company stated that the evidence for those concerns were inconclusive. As Dr. Kelsey continued to stand as a barrier to the approval of thalidomide in the United States, cases of severe abnormal birth defects around the world began to increase at an alarming rate.
“I was the newest person there and pretty green… so my supervisors decided, ‘Well, this is a very easy one. There will be no problems with sleeping pills.’ ”Dr. Frances Oldham Kelsey
The Fall of Thalidomide
By November 1961, the devastating effects of thalidomide were finally recognized by health authorities worldwide, and it has taken 5 years since the first thalidomide baby for the medical community to recognize the link between thalidomide and birth defects. Germany was the first country to pull thalidomide from the market, and other countries began issuing warnings and by March 1962, thalidomide had been banned in nearly all countries it was marketed in. The devastating impact of thalidomide was described as “the biggest man-made medical disaster ever,” with over 10,000 babies born with phocomelia, a severe malformation of the arms and legs. Most of the babies died before they reached a year old, as some were born without limbs or ears, and had deformities with their eyes, esophagus, or intestines. As Dr. Kelsey had suspected, scientists discovered that thalidomide could cross the placental barrier and hinder development in fetuses because they were unable to metabolize the drug. This allowed thalidomide to degrade transcription factors, particularly SALL4, which interfered with the development of limbs in fetuses.
Thanks to Dr. Kelsey’s determination and unwillingness to compromise science and patient safety under pressure, the United States only saw 17 births with thalidomide-related defects from the samples of thalidomide given by Richardson-Morrell, compared to the great worldwide toll it had taken where it was estimated that 100,000 babies were affected by thalidomide. In March 1962, Richardson-Merrell pulled their application for FDA approval as an increasing number of countries began banning thalidomide. Dr. Kelsey’s role in saving countless lives and preventing this devastating tragedy in the United States was unknown at first, but when Estes Kefauver, a senator from Tennessee who advocated for drug laws, informed The Washington Post of her contributions, this launched Dr. Kelsey into global coverage, and she was hailed as a hero. However, Dr. Kelsey insisted that others at the FDA, including her pharmacologist, Oyam Jiro, her chemist, Lee Geismar, and her bosses who had backed her even when pressured by Richardson-Merrell, were also deserving of the credit.
Dr. Kelsey’s work shed light to the public about the need for stronger drug laws, so on October 10th, 1962, the Kefauver-Harris Amendments were passed, which required drug manufacturers to prove the safety and efficacy of the drug, disclose side effects of the drug, and prevent generic drugs from being marketed as a new, breakthrough drug. This was the first amendment that required proof of effectiveness, as previous drugs were only required to be safe for humans, and the thalidomide tragedy was the primary reason that this amendment was passed. By July 1962, the FDA’s Bureau of Field Administration took to contacting each of the 1,000 physicians who had received samples of thalidomide personally in order to remove thalidomide from circulation, and on August 1st, 1962, President John F. Kennedy urged people to check their medicine cabinets for thalidomide to turn over to the FDA. Finally, on August 7th, 1962, Dr. Frances Kelsey was awarded the President’s Award for Distinguished Federal Civilian Service by President Kennedy, the highest award given to a civilian in the United States. President Kennedy stated, “Her exceptional judgment in evaluating a new drug for safety for human use has prevented a major tragedy of birth deformities in the United States. Through high ability and steadfast confidence in her professional decision she has made an outstanding contribution to the protection of the health of the American people.” She continued to be recognized for her role in preventing the thalidomide tragedy throughout her career, and in 2015, Dr. Kelsey passed away at the age of 101.
Thalidomide – A Redemption Arc or Forever Villain?
When the devastating effects of thalidomide on fetuses were discovered, the public was horrified by the circumstances and lack of testing that had led to the thalidomide tragedy. Many expected thalidomide to be gone for good. But in 1980, thalidomide was discovered to be a powerful drug against angiogenesis – a process in which cancer cells form new blood vessels to support tumor growth – which could be developed into an effective treatment against multiple myeloma and other cancers. To illustrate, a derivative of thalidomide, lenalidomide, is capable of disabling the transcription factors in multiple myeloma cells that cause excessive cell growth, showing promise as a “template” for developing drugs that target transcription factors. In 2006, the use of thalidomide and dexamethasone was approved by the FDA through fast-tracking to treat multiple myeloma. In addition, in the mid-1960s, research into thalidomide found that it had an anti-inflammatory effect by inhibiting the tumor necrosis factor-α, which is an inflammatory cytokine. By 1998, the FDA had approved the use of thalidomide for erythema nodosum leprosum (ENL), which are inflammatory skin lesions as a complication of leprosy caused by the immune system.
Despite this discovery of thalidomide as a potential drug for other devastating diseases, some countries saw a resurgence of phocomelia caused by thalidomide in infants born to those who had taken thalidomide to treat other conditions. In particular, in 1965, thalidomide was re-approved in Brazil to treat ENL, where in a span of five years, 5.8 million thalidomide tablets were distributed across Brazil. But in a study of 17.5 million birth records in Brazil, it was found that over 100 babies were identified to have birth defects caused by thalidomide as the rate of birth defects correlated with the use of thalidomide to treat leprosy. Most of these cases occur in rural Brazil, as poor medical education and sharing of drugs is stated as a reason for the birth defects caused by thalidomide. Despite these risks, many doctors still prescribe thalidomide because they believe the benefits outweigh the risks.
But what about the thalidomide babies today? For those who were affected by thalidomide, many suffer from pain, reduced mobility, tingling, numbness, and poor mental health on a daily basis. For years, victims of thalidomide never received compensation or an apology from Chemie Grünenthal, even though many needed expensive treatments and prosthetics because of their disabilities. In 1968, a legal battle by the families affected by thalidomide finally settled that the company manufacturing the drug in the United Kingdom, Distillers, would pay 62 families a monetary sum for the damages caused by thalidomide. Many were shocked by the inadequacy of the compensation to the thousands of other babies born with birth defects from thalidomide, so since then, various news outlets and nonprofit organizations have been fighting for the rightful compensation of thalidomide survivors. More than half a century after the thalidomide tragedy, Chemie Grünenthal finally issued an apology after being silent for 50 years, where Herald Stock, the chief executive officer of Chemie Grünenthal, stated, “We wish that the thalidomide tragedy had never happened. We see both the physical hardship and the emotional stress that the affected, their families and particularly their mothers, had to suffer because of thalidomide and still have to endure day by day.”
The thalidomide tragedy was caused by corrupt medical science and insufficient tests, becoming undoubtedly one of the worst man-made medical disasters faced by mankind. However, it also held a glimmer of triumph when it helped shed light on the importance of stricter drug regulations, as well as the professionalism held by Dr. Frances Kelsey that prevented the devastating crisis from occurring in the United States. Yet, with the potential uses for thalidomide in treating serious diseases such as cancer and leprosy, the ghost of the thalidomide tragedy still holds as people consider the struggles faced by thalidomide victims today caused by thalidomide’s teratogenic effects with the possibility of a redemption for thalidomide.
Oldham Kelsey, F. (n.d.). Autobiographical Reflections. Silver Spring, Maryland; Food and Drug Administration. https://www.fda.gov/media/89162/download (Note: This is Dr. Frances Kelsey’s autobiography, where she describes the obstacles that she faced as a woman in science!)
Fintel, B., Samaras, A. T., & Carias, E. (2009, July 28). The Thalidomide Tragedy: Lessons for Drug Safety and Regulation. Helix Magazine. https://helix.northwestern.edu/article/thalidomide-tragedy-lessons-drug-safety-and-regulation.
Thalidomide. Science Museum. (2019, December 11). https://www.sciencemuseum.org.uk/objects-and-stories/medicine/thalidomide.
Tantibanchachai, C. (2014, April 1). US Regulatory Response to Thalidomide (1950-2000). The Embryo Project Encyclopedia. https://embryo.asu.edu/pages/us-regulatory-response-thalidomide-1950-2000.
Thomson Reuters. (2012, September 12). Thalidomide’s big lie overshadows corporate apology . Reuters. https://www.reuters.com/article/idUS387880049020120912.
Bernstein, A., & Sullivan, P. (2015, August 7). Frances Oldham Kelsey, FDA scientist who kept thalidomide off U.S. market, dies at 101. The Washington Post. https://www.washingtonpost.com/national/health-science/frances-oldham-kelsey-heroine-of-thalidomide-tragedy-dies-at-101/2015/08/07/ae57335e-c5da-11df-94e1-c5afa35a9e59_story.html.
Geraghty, K. (2001, July 1). Protecting the Public: Profile of Dr. Frances Oldham Kelsey. AMA Journal of Ethics. https://journalofethics.ama-assn.org/article/protecting-public-profile-dr-frances-oldham-kelsey/2001-07.
McFadden, R. D. (2015, August 7). Frances Oldham Kelsey, Who Saved U.S. Babies From Thalidomide, Dies at 101. The New York Times. https://www.nytimes.com/2015/08/08/science/frances-oldham-kelsey-fda-doctor-who-exposed-danger-of-thalidomide-dies-at-101.html.
Kennedy, S. (2015, February 20). FDA Kefauver-Harris Amendment (1962). IMARC Research. https://www.imarcresearch.com/blog/bid/361199/FDA-Kefauver-Harris-Amendment-1962.
Kefauver-Harris Amendments Revolutionized Drug Development. Regulatory Doctor. (n.d.). https://regulatorydoctor.us/the-kefauver-harris-amendments-1962/.
National Institutes of Health. (2015, June 3). Dr. Frances Kathleen Oldham Kelsey. U.S. National Library of Medicine. https://cfmedicine.nlm.nih.gov/physicians/biography_182.html.
McNeill, L. (2017, May 8). The Woman Who Stood Between America and a Generation of ‘Thalidomide Babies.’ Smithsonian.com. https://www.smithsonianmag.com/science-nature/woman-who-stood-between-america-and-epidemic-birth-defects-180963165/.
Fischer, E. (2018, August 1). After 60 years, scientists uncover how thalidomide produced birth defects. Dana-Farber Cancer Institute. https://www.dana-farber.org/newsroom/news-releases/2018/after-60-years–scientists-uncover-how-thalidomide-produced-birth-defects/.
Kaelin Jr., W. G. (2013, November 28). Scientists discover how thalidomide-like drugs fight cancer. Dana-Farber Cancer Institute. https://www.dana-farber.org/newsroom/news-releases/2013/scientists-discover-how-thalidomide-like-drugs-fight-cancer/.
Rehman, W., Arfons, L. M., & Lazarus, H. M. (2011). The rise, fall and subsequent triumph of thalidomide: lessons learned in drug development. Therapeutic advances in hematology, 2(5), 291–308. https://doi.org/10.1177/2040620711413165
Guardian News and Media. (1968, February 20). Thalidomide babies to get ‘substantial damages’. The Guardian. https://www.theguardian.com/theguardian/1968/feb/20/fromthearchive.
Gray, G. (2015, December 7). Why did thalidomide’s makers ignore warnings about their drug? The Conversation. https://theconversation.com/why-did-thalidomides-makers-ignore-warnings-about-their-drug-47092.
What is Thalidomide? Thalidomide Victims Association of Canada. (n.d.). https://thalidomide.ca/en/what-is-thalidomide/.
About Thalidomide. Thalidomide Trust. (2021, July 2). https://www.thalidomidetrust.org/about-us/about-thalidomide/.