Here’s What Thalidomide Taught Us About the Importance of Thorough Drug Testing With Animal Models

A sleeping pill pregnant women once used to relieve morning sickness is now a reminder of the importance of preclinical tests with animals and safety regulations.

Pregnant women used thalidomide in the late 1950s and early 1960s to treat nausea and sleeplessness. The treatment led to birth defects in about 10,000 children worldwide, mostly in Europe, Australia, Canada and Japan. Over 40 countries marketed the drug.

“Within a short time after its withdrawal from the market due to its suspected association with fetal abnormalities, the drug was shown to produce fetal toxicity in laboratory animals. Had there been more extensive testing on laboratory animals before the drug was launched, the disaster could have been avoided,” Jack Botting, former science director of the U.K.-based Research Defence Society and a pharmacologist by training, wrote in the abstract of the 2002 article “The History of Thalidomide” in Drug News & Perspectives.

Affected babies suffered physical disabilities and typically did not fully develop limbs. Thalidomide exposure is estimated to have caused tens of thousands of miscarriages.

Thalidomide was not on the market in the U.S. at the time because the Food and Drug Administration (FDA) put U.S. drug maker Richardson-Merrell’s 1960 drug application on hold. Dr. Frances Oldham Kelsey, a reviewer at the FDA, requested more data on its effects during pregnancy after reports out of Germany showed that people who took thalidomide experienced peripheral neuritis and other side effects.

Kelsey delayed approval after noting a lack of diligent scientific research. She took necessary precautions that prevented great tragedy in the U.S. The FDA never approved the drug for use in pregnant women.

However, doctors gave thalidomide tablets to as many as 20,000 people, including several hundred pregnant women, during U.S. clinical trials. Seventeen women in the states reported they had deformed infants after taking the medicine, according to the Embryo Project Encyclopedia at Arizona State University.

German pharmaceutical company Chemie Grünenthal launched the sedative drug in Europe in 1957. The company marketed the drug as the first safe sleeping pill. Most countries banned thalidomide by 1962.

This marked a pivotal point in the U.S. in the animal research field. The incident, in part, pushed U.S. officials to put in place more rigid guidelines for drug sponsors and manufacturers. The U.S. government and other international regulatory bodies put in place toxicity testing (or safety assessment) protocols that paved the way for our modern drug approval process, which involves animal testing.

Congress passed the Kefauver-Harris Amendments in 1962 to the Federal Food, Drug and Cosmetic Act to ensure the safety of drugs.

The FDA can mandate drug sponsors or manufacturers to provide reports on nonclinical tests, which may include animal models and adjunct methods, to justify any proposed clinical testing, according to federal law.

Chemie Grünenthal appeared to have conducted research of the drug with rats and mice, but reportedly never tested thalidomide with pregnant animals premarket.

“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 nonpoisonous,” University of Stockholm scientists reportedly said in 1965.

Dr. Heinrich Mückter, who discovered thalidomide in 1954, and his associates “tried to hoodwink the reader by creating a false impression of the scope of their tests,” the scientists said.

Trials with rabbits demonstrated the fetal toxicity of the drug in 1962, months after the withdrawal of thalidomide from the German market. These results were confirmed through additional trials with several other species of small mammals and eight species of monkeys over the following 10 years.

The German drug maker issued its first apology to the victims and families in 2012.

“We ask that you regard our long silence as a sign of the shock that your fate caused in us,” Grünenthal Group CEO Harald Stock said, according to an English translation of his remarks.

The Misleading Animal Rights Narrative

Some animal rights groups use the thalidomide tragedy to argue against the necessity of animal research, claiming that because the drug was tested with some animals before its release, animal studies are unreliable. However, this argument ignores critical facts about the history of thalidomide.

The thalidomide tragedy could have been avoided if researchers had studied the drug’s effects with pregnant animals before releasing it to the market. More thorough animal testing could have revealed the drug’s teratogenic, or birth defect-causing, effects. That’s a far cry from animal activists who misleadingly argue that thalidomide proves animal testing is unreliable.  

It was only after the disaster that scientists conducted extensive studies, discovering that thalidomide caused birth defects in animals such as rabbits and primates. The tragedy led to the implementation of strict reproductive toxicity testing with animals, which is now a cornerstone of modern drug development.

Here’s what we can learn from the thalidomide incident:

The incident shows the intricacy of the animal testing process. It ultimately highlights how complex the issue is and how important animal models are throughout the drug testing process.

The tragedy “stimulated a tremendous increase in animal testing requirements for new drugs and a range of other substances,” WellBeing International President Andrew N. Rowan wrote in the 1984 book “Of Mice, Models, and Men: A Critical Evaluation of Animal Research.” “In particular, it also ensured that any new drug likely to be taken by females of reproductive age would be tested for its potential to cause fetal malformations (World Health Organization 1967).”

Research on thalidomide continued. The FDA approved the drug in 1998. It’s used to treat issues such as the blood cancer multiple myeloma and inflammation associated with leprosy.

The FDA also put pregnancy ratings in place in 1979. The federal agency updated its five letter risk categories to a new prescription drug labeling system in 2015, which includes information about risks and data associated with pregnant women and nursing mothers.  

Ultimately, drugs need to be safe and effective before companies stock them on the shelves, and this can only be done with thorough testing with the appropriate animal models.

(featured image credit: Alexey Novikov/Adobe Stock)