Thalidomide, the Poster Child for Drug Safety and Testing

The release of the COVID-19 vaccine has stirred renewed interest in drug safety and testing, and no drug prompted more interest in safety than the drug thalidomide, whose release in 1956 led to what has been called the "biggest manmade medical disaster ever."

In 1952, the Swiss pharmaceutical company Chemical Industry Base, more commonly known by its acronym CIBA, synthesized a new drug, which it called thalidomide. In 1957, the drug was acquired by the German company Chemie Grünenthal whose scientists determined that thalidomide was a particularly good anti-nausea, or antiemetic, medication.

By 1957 the company was marketing thalidomide as ideal for use during pregnancy to control morning sickness, and you could buy it over the counter, without the need for a prescription. Chemie Grünenthal also marketed thalidomide as effective against insomnia, coughs, colds, and headaches. Under license by Chemie Grünenthal, 14 separate pharmaceutical companies began marketing thalidomide in 46 countries under 37 different brand names.

The first signs of trouble

Soon, strange reports began appearing of stillborn children, and babies born with peculiar abnormalities to mothers who had taken thalidomide during the first and second trimesters of their pregnancies. At that time, most drugs were not routinely tested for their potential effect on fetuses because it was thought they couldn't pass through the placental barrier.

By 1959, the reports prompted an end to thalidomide's over the counter sales, but it wasn't until November 1961 that the drug was removed from sale altogether.

Prior to 1961, thalidomide was being sold in the UK by The Distillers Company Ltd, who marketed it in the UK, Australia, and New Zealand under the brand name Distaval, as a remedy for morning sickness. An ad for the drug stated, "Distaval can be given with complete safety to pregnant women and nursing mothers without adverse effect on mother or child ... Outstandingly safe Distaval has been prescribed for nearly three years in this country."

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In the U.S., representatives from Chemie Grünenthal approached Smith, Kline & French, the company now known as GlaxoSmithKline (GSK), with a request to market and distribute thalidomide in North America. GSK declined, but in 1958, the Richardson-Merrell Pharmaceuticals Co. agreed to license the drug for sale in the U.S.

When Richardson-Merrell submitted the drug for approval to the U.S. Food and Drug Administration (FDA) in September 1960, something unusual happened. Despite thalidomide's approval in Canada, and over 20 other countries worldwide, FDA pharmacologist and physician Frances Oldham Kelsey rejected the application for thalidomide on the grounds that it lacked sufficient evidence of safety through rigorous clinical trials.

Kelsey denied the approval not once but six times, however, that didn't stop Merrell from testing the drug in the U.S. In all, 17 children were born in the U.S. with limb malformations.

In Canada, thalidomide went on sale on April 1, 1961, and it wasn't until March 2, 1962 that it was removed from the Canadian market.

The effects of thalidomide

It was later determined that the day on which a woman took thalidomide during her pregnancy determined the type of damage her fetus suffered. If the drug was taken on the 10th day, it caused brain damage, if it was taken on the 21st day, it caused eye damage. When taken on the 22nd day of pregnancy, thalidomide damaged the ears and face of the fetus, while if it was taken on day 24, it damaged the fetus's arms.

If the drug was taken up to day 28, the legs of the fetus would be damaged, however, no damage would be caused if thalidomide was taken after 42 days of gestation. Thalidomide caused a syndrome known as thalidomide embryopathy, or TE, and around 40% of babies born with TE died before their first birthday. It is estimated that thalidomide caused the deaths of approximately 2,000 children and serious birth defects in over 10,000 children, 5,000 in West Germany alone. Besides limb deformations, thalidomide also caused eye, urinary tract, and heart problems.

Approximately 2,000 British babies were born with thalidomide-caused defects, with half of them dying before their first birthday. 466 children survived until 2010. In 1968, Distillers Company agreed to a multi-million-pound financial settlement to thalidomide victims. In December 2009, the UK government-funded thalidomide survivors with £20 million to be distributed through The Thalidomide Trust.

In July 2012, an Australian woman who had been born without limbs was awarded several million Australian dollars after she sued Chemie Grünenthal. In February 2014, the Supreme Court of Victoria created a settlement of $89 million AUD to be distributed to 107 victims of thalidomide living in Australia and New Zealand.

The experience of thalidomide prompted many countries to adopt tougher rules for the testing and licensing of new drugs. In the U.S., it led to the passage in October 1962 of the Kefauver Harris Amendment which required pharmaceutical companies to demonstrate the efficacy of new drugs, report adverse reactions to the FDA, request consent from patients participating in clinical studies.

The E.U. addressed the issue in 1965 with its Directive 65/65/EEC1. In the UK, the experience of thalidomide led to the Medicines Act of 1968. 

On August 7, 1962, Frances Oldham Kelsey became the second woman to receive the President's Award for Distinguished Federal Civilian Service which she was awarded by President John F. Kennedy. Incredibly, Kelsey continued working at the FDA until 2005 when she was 90 years old. In 2010, the FDA created the Kelsey Award, which is given annually to a deserving employee.

Thalidomide survivors

Many people have overcome the defects caused by thalidomide and gone on to have rich and productive lives. They include the UK's Lorraine Mercer MBE, who was born with neither arms nor legs, but she carried the Olympic Torch during the London Olympic Games in 2012. English rock musician Mat Fraser, whose arms were affected, produced a 2002 documentary entitled Born Freak which concerned disabled performers.

German filmmaker Niko von Glasow created the 2008 documentary NoBody's Perfect which examined the lives of 12 people who had been affected by thalidomide. Internationally known German bass-baritone Thomas Quasthoff describes himself as "1.34 meters tall, short arms, seven fingers — four right, three left — large, relatively well-formed head, brown eyes, distinctive lips; profession: singer."

In 1998, Thalidomide was approved for use in the U.S., and it appears on the World Health Organization's List of Essential Medicines. Thalidomide is used to treat several forms of cancer, including multiple myeloma, graft-versus-host disease, and skin conditions resulting from leprosy. Anyone receiving the drug must produce proof of contraceptive use.