The Origins of Modern Drug Development and Regulation: Grünenthal’s Thalidomide
Well, this is certainly an unusual post. That being said, let’s get into it.
Let’s rewind to June 1961. A woman in Germany, heavily pregnant, was brought to a hospital after having labor pains and minor contractions. On the way to the hospital, she reflected upon the past few months of her pregnancy. Things had gone relatively smooth up until that point, because she rested well, read nutrition magazines, took regular strolls, and did everything an expecting mother was supposed to do to ensure her child’s health. The only concern in her entire pregnancy was her consistent severe bouts of morning sickness in her first and second trimester. But that had been resolved after popping a pill in her third trimester, as prescribed by her doctor. She was feeling great, (though in a tremendous amount of pain) as she was being wheeled to the operating room.
Unfortunately, her happiness and joy turned into worry and distress once she gave birth. Her child’s limbs were shortened, specifically his arms and hands, which were missing elbows and several fingers. His legs were no different, both shortened, missing kneecaps and toes. The lack of joints and phalanges baffled the doctors, who immediately were convinced that this was an extreme case of malformation, also known as phocomelia. Presenting diagnosis after diagnosis, doctors tried to alleviate the birth defects as best as they could with pain medication and psychological treatment. But by then, the damage was already done. This is the story of Frederick Dove, a BBC World Service Representative who was born with severe birth defects in Hamburg, Germany. Alarmingly, he wasn’t the only one who was diagnosed with phocomelia during that time.
In the late 1950’s and early 1960’s, over 20,000 children were diagnosed with phocomelia and microcephaly. Around this time, miscarriage and infant deaths increased by 80,000, with reasons at the time unknown. Out of the 10,000 children that were born with these defects in Germany, only 3,000 live today.
But why did phocomelia cases multiply so suddenly? In 1961, a doctor by the name of Dr. William McBride had wondered why birth defects rose significantly in Southern Australia, specifically in his patient’s children. After analyzing patient prescription history and international data, Dr. William McBride pinpointed the cause. Turns out, a certain morning sickness pill was to blame.
Thalidomide (Thalomid), was first marketed by a German company named Grünenthal in 1957. Originally advertised as an over-the-counter remedy for anxiety, insomnia, and “tension”(depression), the company quickly rebranded the product as a “morning sickness” pill due to its anti-emetic effect in pregnant women. By stimulating certain T-cells and suppressing a cytokine cell signaling protein (TNF), thalidomide acts as an immunomodulatory medication, specifically for immunotherapy. It was designed to be non-toxic, barely having “enough potency to kill a rat” (Helix, 2009). Even today, thalidomide is approved on the WHO’s List of Essential Medicines as of 1998, despite having side effects including a wide array of maladies, such as blood clots, tumors, and peripheral neuropathy. Once taken, thalidomide can affect all of the patient’s organs, including gestational organs such as the placenta. The first 40 days of conception corresponds to rapid embryonic development, which coincides with the first trimester. Since the placenta is the only medium of nourishment and nutrients (not to mention also delicate), tampering with narcotics can cause significant damage in the development and maturation of the child. Even after birth, the mortality rate for children with thalidomide induced phocomelia was 40%; most of the children died in utero, which explains the increased miscarriage rates.
Companies and the pharmaceutical industry were at a huge loss. Due to the rapid influx of PTSD and other anxiety and stress related ailments from World War II, people sought business by manufacturing drugs and other narcotics, even if their company had no prior experience in the medical community. Grünenthal itself was a well established soap business, during and after the war. The exposure of “anti-x” pills left those who were profoundly impacted by economic and personal loss post-war under the impression that narcotics could provide them salvation, even if it was short term. Hence, the “popping a pill” culture was born. As people began using more and more narcotics and over-the-counter tranquilizers to cope with physical and emotional pain, business boomed. Because of high demand, companies and incorporations weren’t very meticulous in their drug testing regulations in order to pump out more products. At the time, they weren’t aware of the repercussions of having weak testing methods, until this entire tragedy happened.
After having tens of thousands of children affected, the international medical and pharmaceutical industries realized the severity of the predicament they had caused in their respective countries. Surprisingly, the United States of America reported no cases of thalidomide induced phocomelia. The woman responsible for this was Dr. Frances Oldham Kelsey, a pharmacologist and physician on the FDA’s reviewing board. She had refused to authorize thalidomide due to the lack of testing and general content information from Grünenthal. Though under tremendous pressure from the government and Grünenthal (who had submitted thalidomide for approval six times), Dr. Kelsey demanded trials first before authorization. A total of 17 cases of thalidomide embryopathy was reported in the results of the trial. As a result, Dr. Kelsey received numerous accolades and praise from the Kennedy Administration, including the President’s Award for Distinguished Federal Civilian Service. Promptly after, the Kefauver Harris Amendment was passed, stating that drug companies are required to provide prove of the effectiveness and safety of their drugs prior to approval, provide accurate information about side effects, and stopped the manufacturing of cheap, harmful drugs. This was the first time where a “proof of efficacy” was required in history. A myriad of other requirements was added on to the amendment, such as patient trial consent, reports on patient reactions, and the knowledge of the drug’s chemical composition.
Today, when a new illness is discovered, manufacturers and medical professionals make sure that the medication passes all phases of drug testing trials, so as to avoid another massive man-made medical disaster (no matter how much the pressure or stress from the public). This is all due to Dr. Kelsey, and the Kefauver Harris Amendment, which ultimately revolutionized the way drugs are manufactured and approved.
BIBLIOGRAPHY
Kefauver Harris Amendment. (2020, May 13). Retrieved July 20, 2020, from https://en.wikipedia.org/wiki/Kefauver_Harris_Amendment
Vargesson, N. (2015, June). Thalidomide-induced teratogenesis: History and mechanisms. Retrieved July 20, 2020, from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4737249/
Health Association, C. (2012, October). Kefauver-Harris Amendment Revolution. Retrieved July 19, 2020, from https://regulatorydoctor.us/wp-content/uploads/2014/12/Kefauver-Harris-Amendments-Revolutionized-Drug-Development.pdf
Carolyn J Stephens on Aug 21, 20, M., 26, C., 3, K., 24, A., 19, A., . . . 25, C. (n.d.). Helix Magazine. Retrieved July 20, 2020, from https://helix.northwestern.edu/article/thalidomide-tragedy-lessons-drug-safety-and-regulation (+image)
