It’s time for a new article in my ‘science stories‘ series.
We already talked about Elizabeth Holmes, who fooled everyone in the Silicon Valley with a machine that never worked, and Henrietta Lacks, who is at the origin of the first immortal cell line.
We’re now in for another important science tale : the Thalidomide tragedy, and how it shed light on the importance of drug regulation and monitoring.
Creation
Everything began in 1952, when “Gesellschaft für Chemische Industrie Basel“, a Swiss company, synthesized Thalidomide. For the anecdote, this company will later be involved in the foundation of Novartis, one of the largest pharmaceutical corporation in the world. At the time, they did not observe any effects in animals and thus discarded it.
A German company, Chemie Grünenthal, then acquired the chemical in 1957. For the (way heavier) anecdote, this company was involved with former Nazi Party members and concentration camps leaders. As the chemical formulation was close to Glutethimide, a sedative, the scientists thought they could use it for the same purpose. They tested the toxicity on animals, but it was never tested on pregnant animals or women.
While testing and researching the product, they found out that Thalidomide had a particularly effective antiemetic property as well. Therefore, in 1957, they launched the product and marketed it for insomnia, colds, coughs and morning sickness.
See where this is going ?
Context
So we are in Europe, in 1957. Drug regulation was not was it is today. A strong belief at that time was that no drug taken by a pregnant woman could pass the placental barrier and harm the foetus… Thus, the use of medication during pregnancy was not really controlled. Drugs were not tested for teratogenic effects.
Europe was not the only faulty continent, as Thalidomide was then accepted and distributed in the United Kingdom (1958), Japan (1958), Norway (1959), Canada (1961) and several other countries.
It is important to note that despite being behind on a lot of topics now, at the time, the United States did good. The US Food and Drug Administration (FDA) refused to approve Thalidomide because of the lack of sufficient research.
It’s Dr. Frances Oldham Kelsey, who, thanks to her rigor and integrity, prevented the drug from being marketed in the US and saved countless of lives. Having been made aware of the risks of peripheral neuropathy associated with Thalidomide, Dr. Kelsey had specifically requested that the American distributor demonstrate to the FDA that the drug was safe for pregnant women (evidence that the company never provided, obviously). Kelsey will later be awarded the President’s Award for Distinguished Federal Civilian Service by President Kennedy and inducted into the National Women’s Hall of Fame in 2000.
Complications
So, back to 1957. Thalidomide is now distributed widely as a wonder drug for morning sickness in pregnant women. However, reports of abnormalities in children being born to these mothers began to appear pretty soon. The drug was actually responsible for teratogenic deformities.
The main defect was a congenital condition called phocomelia, that involves malformations of human arms and legs which results in a flipper-like limb.
The infants that were exposed to Thalidomide during development phases actually had a 40% chance of survival. The McMredie–McBride hypothesis explains that the limbs of the infants become malformed as a result of the thalidomide harming the neural tissue—simply because the neural tissue has such a large impact on formation and development of the limbs.
The severity and location of the deformities depended on how many days into the pregnancy the mom was before beginning treatment, with the time-sensitive window occurring approximately between day 20 and day 36 post-fertilisation. As Thalidomide was sold as an over-the-counter morning sickness drug, you can understand how easily it was distributed to pregnant women.
Reactions
It took until November 1961 for the drug to start being taken off the market.
The first concerns were raised by medical staff simultaneously in Australia and Germany.
Australia
The first reported concern was made by a midwife named Pat Sparrow, who was working at Crown Street Women’s Hospital in Sidney. She suspected that the drug was causing birth defects, as it was the only link between three cases she had recently seen. She confided in William Griffith McBride, who was the obstetrician on duty.
He then apparently contacted the British drug distributor in June 1961, but nothing was done before December 16, 1961, when he published a short letter in the Lancet, a peer-reviewed medical journal.
Here is an excerpt :
Thalidomide and congenital abnormalities
Sir, – Congenital abnormalities are present in approximately 1.5% of babies. In recent months I have observed that the incidence of multiple severe abnormalities in babies delivered of women who were given the drug Thalidomide during pregnancy […] to be almost 20%.”
As a side note, McBride took full credit for the discovery (not cool, dude). As such, he was awarded a medal and prize money by a prestigious French institute in 1971.
But as we all know, you reap what you sow… Later in his life, McBride was involved in several trials with the pharma industry blaming him for medical malpractice and scientific fraud for falsifying data in a paper that claimed that the drug Debendox was also responsible for birth defects. As a result, he was struck off the Australian medical register in 1993 (never underestimate karma, William).
Germany
German pediatrician Widuking Lenz was also one of the first to suspect the link in 1961.
Here is what he had to say about that discovery, at the beginning of a lecture given later, in 1992 :
“I had suspected Thalidomide to be the cause of an outbreak of limb and ear malformation in Western Germany for the first time on November 11, 1961, and by November 16, I felt sufficiently certain from continuing investigations to warn Chemie Grünenthal by a phone call. It took ten more days of intensive discussions with representatives of the producer firm, of health authorities, and of experts before the drug was withdrawn, largely due to reports in the press. Dispute on the question, whether Thalidomide did or did not cause malformations was going on for months, though independent confirmation of Dr. McBride’s and my observations rapidly accumulated.”
Consequently, Thalidomide was withdrawn from the market before the end of the year 1961 by German and English distributors.
Rest of the world
Unfortunately, in other countries like Belgium, Brazil, Canada, Italy and Japan, Thalidomide continued to be sold for several months. In 1962, Thalidomide was finally withdrawn everywhere.
Consequences
Experts estimate that the Thalidomide tragedy led to the death of approximately 2000 children and serious birth defects in more than 10’000 children, with over half of them in West Germany (as East Germany never accepted the drug). Those who survived had limb, eye, urinary tract, and heart defects. It was absolutely devastating for everyone involved.
In 1968, Chemie Grünenthal officials were charged with negligent homicide and injury in West Germany. The trial began and closed after the company settled with the victims.
Around the world, the victims and their families entered into class action legal suits, or threatened actions, against the various drug companies who manufactured and/or distributed the drug, and they were eventually awarded settlements. In most countries, these settlements included monthly or annual payments based on the level of disability of the individual.
Drug regulation and monitoring effects
The birth defects and lost lives of Thalidomide were absolutely tragic, but it at least led to the development of greater drug regulation and monitoring in many countries, to ensure that this disaster would never happen again.
Many countries introduced tougher rules for the testing and licensing of drugs :
- United States : Kefauver Harris Amendment in 1962
- Europe : Directive 65/65/EEC1 in 1965
- United Kingdom : Medicines Act in 1968
It also shed a light on the exclusion of women and pregnant women in most pharmaceutical trials, which was a problem in itself.
The Thalidomide tragedy : Conclusion
This story is a great example of how a tiny oversight at the beginning of a scientific process can snowball and create terrible consequences for thousands of lives. It is also a lesson on how every scientific roles matter : even if you’re a lower level chemical scientist, your work could impact so many people. Never think you are above safety procedures and checklists.
We’re also quick to think “it’s safe, it has been through the whole testing process” when we’re taking drugs, but we should always be mindful. And it may seem dumb to repeat that, but always research and read the drug instructions before use, who knows if an oversight occurred…
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