Between 1957 and 1962, more than 10,000 babies were born with physical abnormalities caused by the drug thalidomide. Out of this came stricter regulations for approving new drugs and vaccines that remain in effect to this day.
The story of what some scientists have called “the biggest man-made medical disaster ever” began in West Germany in the 1950s, when researchers at the pharmaceutical company Chemie Grünenthal developed thalidomide.
In July 1956, medical authorities in West Germany licensed the drug for sale without a prescription. Thalidomide had been developed as a sedative or tranquilizer, but people were soon taking it for a range of conditions, including pneumonia, colds, and the flu, as well as to relieve nausea in early pregnancy.
Within a few years, Chemie Grünenthal had licensed 14 pharmaceutical companies to market thalidomide in 46 countries throughout the world under at least 37 brand names.
‘Complete safety’
In the United Kingdom, Distillers Company Biochemicals began marketing the drug, under the name Distaval, in 1958 as a remedy for morning sickness.
Though no evidence from studies in humans supported their claim, the company’s advertisements announced, “Distaval can be given with complete safety to pregnant women and nursing mothers without adverse effect on mother or child.”
Based on standard toxicity tests that Chemie Grünenthal had performed in mice, the company believed that even very high doses of the drug were harmless to humans.
Dr. Alexander Leslie Florence, then a general practitioner in Turriff, Scotland, was the first healthcare professional to publicly question this assumption. In a letter to the BMJ in 1960, he reported that four of his patients had developed severe paraesthesia, a numb or burning sensation similar to pins and needles, in their hands and feet while taking thalidomide.
He wrote:
“Three of the patients have now received no thalidomide for 2–3 months, and there has been a marked improvement in their symptoms, but they are still present. […] It would appear that these symptoms could possibly be a toxic effect of thalidomide.”
The following year, Dr. William McBride, an Australian obstetrician who had helped popularize thalidomide as a treatment for morning sickness, wrote a letter to The Lancet describing “multiple severe abnormalities” in 1 in 5 babies born to people who had taken the drug during pregnancy.
After a federal investigation in Germany concerning a similar increase in congenital abnormalities, Chemie Grünenthal ceased the national distribution of thalidomide on November 26, 1961 — more than 5 years after the drug had become available. U.K. distributors followed suit on December 2, 1961.
By 1962, thalidomide was banned in most countries where it had been sold.
Because it was an ingredient in cough medicines for children, however, the drug remained in medicine cabinets throughout the world long after its withdrawal from the market, according to the Thalidomide Society, in the U.K.
Embryo development
The medical community now recognizes that the drug alters human embryo development if a pregnant person takes it 20–37 days after conceiving.
Thalidomide causes a wide range of developmental differences, one of the most common being phocomelia, which refers to having missing or shortened limbs. The drug can cause a baby’s hands and feet to be differently formed or rudimentary.
Thalidomide also affects the development of organs, including the brain, the eyes, and the auditory system.
Estimates suggest that the drug caused at least 10,000 cases of severe congenital abnormality, leading to the death within months of approximately half of the babies affected. There were also reports of increased rates of pregnancy loss during the period when thalidomide was widely used.
The United States did not see the same rates as Germany or the U.K., for example, due to the vigilance of a pharmacologist at the Food and Drug Administration (FDA) named Dr. Frances Kelsey.
In 1960, Dr. Kelsey refused applications from the William S. Merrell Company to market thalidomide, as a sedative branded Kevadon, citing a lack of evidence regarding its safety in humans and concerns about nerve damage.
Lack of oversight
Even if the results of clinical trials had been available, however, they would not have been reliable, because trials at the time did not require either FDA approval or oversight.
In fact, unbeknownst to the FDA, the company had already distributed 2.5 million thalidomide pills to doctors across the U.S. The doctors had administered them to around 20,000 patients, including 207 pregnant people. More than 1,000 doctors took part in these “clinical trials,” though few monitored the effects of the drug on their patients.
According to the FDA, during this period, there were 17 births with abnormalities linked to thalidomide.
In the U.S., the thalidomide crisis led directly to legal reforms. On October 2, 1962, both houses of Congress unanimously passed the Kefauver-Harris Amendments. Then-president John F. Kennedy signed them into law 8 days later.
In essence, they required manufacturers to provide data from animal experiments and highly regulated trials in humans proving that a drug is safe and effective before putting it on the market.
Key regulatory reforms
The Kefauver-Harris Amendments addressed shortcomings of previous legislation, the 1936 Federal Food, Drug, and Cosmetic Act, which had allowed manufacturers to market a drug if the FDA had not acted within 60 days of an application.
“With the passage of the amendments, the FDA was no longer a helpless bystander while unproven medicines were streaming into pharmacies and onto patients’ bedside tables,” commented former FDA commissioner Dr. Margaret Hamburg in an article about the reforms on the agency’s website.
Among other changes, the amendments:
- require that manufacturers prove the efficacy of drugs before they go on the market and report any adverse reactions
- require that this evidence be based on adequate, well-controlled clinical studies conducted by qualified experts
- require informed consent from study participants
- give the FDA 180 days to approve or reject a new drug application
- allow the FDA to set good manufacturing practices and mandate regular inspections of production facilities
- transfer to the FDA control over prescription drug advertising, which must include accurate information about potential side effects
Meanwhile, in acknowledgment of the fact that thalidomide had been available over the counter, many countries improved the ways that they classified and controlled access to medication.
In the U.K., for example, the 1968 Medicines Act led to a distinction between:
- prescription-only medicines
- medicines available only from a pharmacy, without a prescription
- medicines available in any store, without a prescription
Reporting side effects
The U.K. also established a system for doctors to report previously unknown side effects, called the Yellow Card Scheme. It now allows anyone to report what may be a side effect. The FDA, in the U.S., set up a similar system for consumers, called MedWatch.
The U.K. government also mandated that companies must provide evidence from clinical trials showing that any new drug is safe for use in pregnancy before the drug is marketed to pregnant people.
Another key change was that medications could no longer be approved purely on the basis of animal testing.
Writing about thalidomide in the journal Embryo Today: Reviews, Prof. Neil Vargesson, chair in developmental biology at the University of Aberdeen, in the U.K., charts the resulting transformations in drug testing.
In particular, the response to the crisis highlighted that different species react differently to drugs; scientists found that mice, traditionally used to screen drugs, are less sensitive to the effects of thalidomide than species such as rabbits and nonhuman primates.
Prof. Vargesson writes:
“Since the disaster, drug screening policies have changed to incorporate several species as well as in vitro tests, and there has not been a repeat of the disaster.”
Powerful, effective drugs
It may come as a surprise to learn that thalidomide is still in use today. The FDA have approved it for treating Hansen’s disease, once called leprosy, and multiple myeloma, a type of cancer that forms in white blood cells.
However, since 1998, its prescription has been tightly restricted and regulated by the System for Thalidomide Education and Prescribing Safety program, which educates people who take the drug about its risks.
Powerful drugs by their nature can cause severe adverse effects. The thalidomide tragedy demonstrated the need for strictly enforced regulation of drug testing, marketing, dispensing, and use.
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