Thalidomide, despite its sordid past is undergoing a sort of renaissance and is being manufactured and used worldwide for a variety of illnesses including leprosy
The Thalidomide story had a complex course, full of unintended discoveries, with unforeseen consequences including the elements of an adventure story; heroes and heroines, bad guys, villains, intrigue, deception, antagonists and protagonists, even Nazis.
It was December 25, 1956. In Stollberg, Germany. A young, nervous, to-be Dad was waiting for news from the delivery room. His wife was giving birth. He worked as a chemist for the German pharmacy company Grunenthal. Later, the doctor gave him disturbing news; his child had no arms, and only vestigial flipper-like hands, a condition known as phocomelia, Greek for seal arms.
No one could know that in reality the world had received its first Thalidomide baby. The chemist had been given some samples of his company’s new wonder drug for nausea, especially nausea of pregnancy. Later he would learn that only one such baby had been born in Germany with phocomelia within the last twenty years, and that it was thought to be rare birth defect that ran in families. This is where most narratives of Thalidomide usually start.
But the story began much sooner; in the 1930’s. Persistent investigations by independent investigators and representatives of the England-based Thalidomide Trust have uncovered a different beginning. And, slowly, more and more information is coming to light. And now it’s probably safe to assert there was a very different beginning to this story.
The scope of the Thalidomide disaster was worldwide. Over the course of four years, from 1957 to 1961, it was licensed for manufacture and sales in over 50 countries and was the cause of uncountable miscarriages and still births and over twelve thousand “flipper babies.”
As a result, requirements for new drug applications were changed and the drug companies themselves modernized using more science than anecdote before declaring new drugs safe and effective.
Even after all this time some questions remain: what was its origin and why are its effects so different in humans than in animals?
Drug #4589 will end up being Thalidomide in our story. But before we get there we need to tell the story of Sarin, the deadly nerve gas stockpiled by Germany during the Second World War, and also by the United States and Russia after the war.
In 1938, near the town of Wuppertal Germany, Gerhard Schrader, a chemist, was working for the drug company I. G. Farbin to develop insecticides. He had been interested in some 1932 experiments done by the German biochemist Willy Lange and his graduate student Gerde von Krueger. The role of a chemical called acetylcholine in the transmission of nerve impulses was well known, and the effects of the organophosphate class of drugs, by inhibiting the action of a component of that transmission, acetylcholine esterase, had been investigated in the 1932 experiments. Schrader was trying to use Lange’s work to help him develop insecticides.
The story developed quickly after a laboratory accident occurred. A vial of the experimental insecticide spilled onto a bench causing distressing symptoms in the unprotected scientists. They were salivating and tearing uncontrollably, had a tightness in their throats and dim vision. All survived. At this point, Schrader was required by German law to report his discovery to the German war ministry. Law required any discovery that might be of possible military use to be reported.
Shortly thereafter, in mid-1939, Schrader found himself in occupied France at the Rhone-Poulenc chemical plant helping to produce mass, war-grade, amounts of what was eventually named Sarin. It was one of several reported mass production plants.
The nerve gas Sarin was named after the names of its developers at the French chemical plant Rhone-Poulenc.
S for Gerhardt Schrader
A for Otto Ambrose
R for Rudiger
IN for Vanderlind
Hitler visited one of the plants and when he proposed using the gas he was told the Allies would be able to manufacture much more of it than Germany could. After this, the war ministry instructed the scientists to develop an antidote to Sarin. Documents discovered by the investigative journalist, Carlos De Napoli, clearly show that the job of developing an antidote was given to Otto Ambrose, an executive with the I.G. Farben plant in Germany.
Ambrose was joined by Schrader and together, at the Rhone-Poulenc lab and at other locations did experiments on humans and animals, gathering information on their antidote drug. During their testing of the compound as an antidote to nerve gas, the scientists noted that it was also a very effective sedative and tranquilizer, and that it was impossible to overdose on it.
For their human experimentations Ambrose and Schrader were convicted of war crimes. Ambrose was in prison for eight years and later worked for Grunenthal. Both men died in 1990, within weeks of each other.
And as far as being an antidote for Sarin, a memo dated November 13, 1944 from Fritz ter Meer, an I.G. Farben executive to Karl Brandt, an SS officer and Hitler’s personal physician, stated that a drug referred to as Drug #4589 had been tested and was ready for use. The lab at the Rhone-Poulenc plant where Ambrose had done his original work was in reality producing Thalidomide.
Soon after the war, Rhone-Poulenc and all its secrets were purchased by a German based chemical firm named Astra Laboratories after. The smoking gun in this investigation is a recently discovered 1946 memo from Astra to its subsidiary in Norway which says “We cannot use the name Contergan in your area as rights to the name and the right to distribute it was sold to Grunenthal in an agreement with Rhone-Poulenc shortly after the war.”
Grunenthal has always held that it was the sole inventor of Contergan and that three of its employees developed the drug without any knowledge of earlier work. One of those employees: Otto Ambrose, after he was released from being in prison for his war crime convictions. Grunenthal was founded in 1946 by Alfred and Herman Wirtz, members of the Nazi party who also happened to be twins. Otto Ambrose began working for Grunenthal in 1952 two years before the patent for Contergan was awarded to the drug giant.
The question is, why would a post-war drug concern in Germany want to develop an antidote to Sarin?
Answer: They didn’t. It was thought, because of the findings when the drug was tested during the war, that Contergan could be a powerful antihistamine, and possibly a sedative. During the Grunenthal testing, it was noted it wasn’t a good allergy medicine but it was a very effective sedative/hypnotic and anticonvulsant. And animal testing showed it had a peculiar characteristic of rarely being fatal despite massive overdose. And it was particularly effective for treatment of nausea, including nausea of pregnancy. A curious observation, seen as unimportant at the time, was that human subjects seemed to be well sedated with the drug, while the animals tested didn’t seem to be sedated at all.
It was during these two years that Grunenthal also claimed to have done multiple animal experiments showing absolutely no mutagenic effects, no birth abnormalities. None. Contergan would be marketed as a treatment for nausea of pregnancy. Interestingly, when Grunenthal documents regarding the history and development of Contergan were subpoenaed for the civil actions against the company, it was reported that, regrettably, virtually all had been lost. Every last shred. Not one memo or lab note.
And now we’re up to where the story of Thalidomide usually begins; Christmas day, 1956, and the first seal baby.
Grunenthal claims to have started testing and development of their new wonder drug, Contergan, in 1953 and, as noted above, they thought they would have a antihistamine, but testing showed Contergan was fantastic as a sedative, tranquilizer, even anticonvulsant.
Animal testing showed it was virtually impossible to overdose with it and it was safe in pregnancy—not a single instance of teratogenesis, or malformation, was noted in hundreds of animal subjects. They received a patent in 1954 and began sales October 1,1957. They also licensed other companies for overseas production and sales; a total of 149 countries. Two major players: Distillers Limited of England and Merrell Laboratories of Cincinnati, Ohio.
England received quick approval for sales, in part due to the glowing reports of effectiveness and safety supplied by Grunenthal. They called their new product Distaval and the first packets were sold in April 1958. Merrell’s approval was not so easy, and the drug giant was frustrated by the Federal Drug Administration (FDA). A single low level clerk thought the reports were just too glowing, and she denied repeated applications from Merrell. “The reports are just anecdotal,” she would later write, “Too good, not a single side effect.”
One of the first people to surmise that something was wrong with Thalidomide was a young German lawyer living in Hamburg named Karl Shulte-Hillen. Both his sister and his sister-in-law had recently given birth to babies with phocomelia. He wondered if there was something wrong in his hometown, some contaminant perhaps, that might have affected both mothers. In June of 1961 he called the local medical university, asked for help, and was put in touch with a genetics professor, Widukind Lenz.
Professor Widukind Lenz was the sone of the infamous Dr. Fritz Lenz who, as a member of the Nazi party, had done genetics experiments on prisoners-of-war during the second world war.
Karl Shulte-Hillen with his wife and daughter, Jan. Shulte-Hillen was the attorney who was suspicious of the cause of two phocomelia babies in his neighborhood. From January 1962 Life.
Dr. Lenz was reportedly dubious of the young lawyer’s conviction that something was wrong in Hamburg, but he agreed to research the matter. Looking through birth stastistics for the last 25 years before 1960 he discovered that there had been only one documented case of phocomelia in the entire country. Since 1960 there had been 50. He was no longer dubious. And now convinced, Dr. Lenz tracked down the affected families and carefully interviewed them for any common thread that may have caused the deformities.
At exactly the same time, June, 1961, an Australian obstetrician, William McBride, had become suspicious after he delivered his third baby with phocomelia. He also had asked about a common element in all the cases and quickly concluded Distaval, the English brand name, was the prime suspect.
McBride had access to an animal lab and began experiments to reproduce the deformities. He was unable to induce phocomelia in any of the animal subjects. Nonetheless he went to the Australian manufacturer, DCBAL, and pleaded with them to withdraw Distaval from the market. DCBAL refused, citing the doctor’s inability to reproduce a single birth defect in his lab animals. Also, 23 women who had taken Distaval in their pregnancies delivered normal babies.
It was David and Goliath all over again.
Frances Kelsey, a pharmacologist Ph.D. and a medical doctor, was a new face at the Federal Drug Administration, FDA, office in Chicago. Her first assignment: The New Drug Application, NDA, for Kevadon, the Merrell Company’s Thalidomide version. Still operating under the 1938 Food, Drug and Cosmetic Act, her job was to review the application. She had 60 days after the original filing to notify Merrell of a rejection. Or to approve the drug, she simply would do nothing and the approval was automatic. The original NDA reportedly requested that the Kevadon be approved for pain, nervousness, and nausea of pregnancy or morning sickness.
The 1938 Drug approval law established an imperfect system which also allowed drug companies to conduct clinical trials of new drugs, without approval or consent, or notification of any agency, by distributing them to practicing physicians who would then submit anecdotal reports that would be used to support the NDAs.
But Dr. Kelsey was not impressed with anecdotes. Known as a meticulous methodical worker she would later write that she found the NDA just too good, too subjective, with no actual scientific data. The application had glowing testimonials and summary statements saying animal studies showed no ill effects, but no actual data. Importantly, she also noted the animals studied were not sedated in the slightest. She quickly surmised the effects in drug in humans was obviously different than in animals.
She rejected the original application, citing lack of data. Then she rejected the second request. By February of 1961, she had rejected Merrell a total of five times. The firm was reportedly frustrated by Kelsey, and complained vehemently to her superiors.
In the meantime Merrell continued its clinical trials with gusto. The final numbers showed 1267 physicians had distributed 2.5 million tablets to unsuspecting patients of all types, including pregnant women with morning sickness, a total of 20,000 patients. There were 10 phocomelia births from the U.S. distribution, 7 more cases were eventually determined to be from overseas sources; pregnant women would borrow the medicine from a friend or neighbor who had gotten the drug overseas or in Canada.
Dr. Frances Kelsey, c. 1961
Bottle of Thalidomide used during U.S. clinical trials.
Merrell continued their pressure for an approval of their NDA. As another 60 day deadline approached, Kelsey read a December, 1960 British Medical Journal article that linked Thalidomide to a painful side affect, peripheral neuritis; and the pain didn’t go away when the drug was stopped. What’s more, the effect was known, but never reported by Grunenthal or, more importantly to her, by Merrell. Kelsey was reportedly furious and immediately rejected the NDA again, requesting more data and a list of all the physicians who had given the drug during the clinical trials.
The drug had actually been distributed by Merrell’s marketing division, not its research division, and records were not well kept. A rough estimate of the amount of Thalidomide distributed: Five tons. Two tons of which have never been located.
So it was the peripheral neuritis which prompted the final rejection by Dr. Kelsey, not the birth defects. She was quoted as saying she always had the feeling that Merrell was not being complete candid. And once she determined that the peripheral neuritis complication had been withheld by the drug company her rhetoric heated up. “We are much concerned,” she included in her last rejection,” that apparently evidence with respect to the occurrence of peripheral neuritis in England was known to you but not forthrightly disclosed in your latest application.”
Meanwhile, Dr. McBride was still pressuring his local distributor in Australia to stop selling Distaval. Two more babies with phocomelia had been born in September of 1961. The drug company refused, but it forwarded McBride’s data to Grunenthal, in Germany.
The end was near. Dr. Lenz presented his data to Grunenthal at about the same time the Australian data reached them. They sent out an advisory to practitioners notifying them of the recent data. The German newspaper Welt am Sonntag, within a few days, headlined “Malformations from tablets.” And within a few days Grunenthal issued a recall, taking Contergan off the shelf. Without comment, Richardson-Merrell withdrew its NDA.
Final counts of still births and miscarriages can never be known. Over twelve thousand severely deformed babies were born.
But, despite its sordid past there is a Thalidomide rennaisance. What?
It has the makings of a whole separate article; The rebirth of Thalidomide as a wonder drug, well proven this time, is being manufactured and used worldwide for a variety of illnesses.
Thalidomide’s mechanism of action is thought to be its inhibition of the release of growth factors for new blood vessel formation. That’s why the deformities occurred, the new limb buds on the fetus could not generate a blood supply to the extremities. Still nobody knows why animals had no observable effects from Thalidomide. No sedation, no deformities, nothing. Something is different with humans. Thalidomide has two isomers, mirror images, and it’s known one form is active and the other isn’t. Other than that, no one knows why.
It is still manufactured, sold, and prescribed legally in many countries. Why? Because the same characteristic that made it so teratogenic, the inhibition of new blood vessel formation, makes it remarkably effective in a variety of diseases: Leprosy, Myeloma, AIDS complications, Lupus, Rheumatoid Arthritis, Macular Degeneration, and a few other rare conditions. Patients bedridden by Leprosy reportedly get up and walk painlessly within a few hours of a Thalidomide injection. To some, it appears to be a wonder drug, finally.
Brazil has one of the highest incidence rates of Leprosy in the world. It has legally manufactured and used Thalidomide since 1965 when it was accidentally discovered to reduce symptoms of the ancient disease and promote cures. It has also caused 63 phocomelia cases since 1965.
The most enigmatic question about Thalidomide remains.
Senior Correspondent Jones interviewing former Merrell National Labs executive Claude Griffin, Ph.D., in Texas. Above: Looking at the August 10, 1962 Thalidomide edition of Life magazine.
The reader may have guessed what it is, but first an interview with Claude Griffin, former Richardson-Merrell Vice-President for Global Affairs. Dr. Griffin had joined Merrell in 1970, and he knew most of the top executives who had been with the firm during the Thalidomide scandal.
Using several sources, I had tracked him down and he agreed to be interviewed for Health WorldNet. We met at his comfortable golf course home in north central Texas. He told me his biggest success in his job as vice-president for new drug development was Seldane, the world’s first non-sedating antihistamine.
Griffin: “It was the world’s first billion dollar drug. It helped a lot of people and made their lives a lot easier to live.” He also supervised the development of the first nicotine gum product and worked with several Nobel laureates.
Jones: “In your final position at Merrell you were Vice President of global operations, which included a lot of responsibilities I suppose. What was your greatest success in this management role?”
Griffin: “It wasn’t just me, it was all of us in the business of developing and marketing new drugs. The old way of evaluating drugs by using the anecdotal information obtained by ‘the old boy’ network of practicing physicians doing clinical trials was in need of change when I got to Merrell. Especially after the MER 29 mess.”
MER 29 was Merrell’s drug, developed in the late 1950s, it was the world’s first effective cholesterol lowering agent. It had the disastrous side affect of causing cataracts and Merrell executives were criminally charged with covering up evidence and coercing lab workers into falsifying data.
He talked a little about his company’s Thalidomide trials.
Griffin: “That whole way of doing things had to change. So we did. I had some creative differences with some people in new drug development. But after they retired I was able to bring our company around to a more scientific approach to evaluating our data.” The clinical trials without patient consent or knowledge also stopped by virtue of the 1959 Food and Drug act which required consent and put the burden on the drug companies to show safety and effectiveness.
Griffin: “And when we got microcomputers everything became so much easier. Instead of going through stacks of raw data looking for a trend, I could do it in a few seconds. We could finally show statistical significance. Use statistics and science.”He also gave me some information that I had not run across in my research for this article.
Griffin: “We did do our own animal testing on Thalidomide, thousands of tests, all kinds at different stages of gestation. And there wasn’t one single mutation or defect. Not a single one. I wish I knew why. To this day I don’t know why.”
And regarding the U.S. clinical trials he was emphatic.
Griffin: “All our clinical trials in those days distributed the drugs either with a written warning on the container, or an advisory to the physician not to use on women of childbearing age. It was standard operating procedure.”
The Bottom Line
The Thalidomide story points out the obvious. There are always two sides to a story. It appears that thalidomide has finally found its true calling.
However, the final enigma has never been answered, as far as this writer can determine. And that is: How and why was Thalidomide thought up, developed, and synthesized as a Sarin antidote in the first place? Out of all the possibilities in the world, why Thalidomide. No documents have ever been recovered, no lab notes, no files, nothing regarding what Ambrose and Schrader had been thinking.
None of the chemists and pharmacologists I interviewed for this story had the slightest clue. Thalidomide can be made in various ways. One of the easiest is to alter the substance called Glutamine, which occurs naturally in the body. Glutamine, itself, has nothing to do with acetylcholine function. Ambrose and Schrader never spoke publicly about their experiments and took whatever secrets they had to their final resting places, in 1990.
- Glauberman S, The Real Thalidomide Baby: The Evolution Of The FDA In The Shadow of Thalidomide, 1960 - 1997, Harvard Law School, Food and Drug Law, Winter 1997
- Lutz K, From Tragedy to Triumph: The Approval of Thalidomide, Harvard Law School, 1962
- Levy A, Nazis developed Thalidomide and tested it on concentration camp prisoners, author claims, MailOnline, February 08, 2009
- Frances Oldham Kelsey, WikiBooks
- von Moos R, Thalidomide: from tragedy to promise, Swiss Med Weekly, 2003, 133: 77-87
- The Thalidomide Trust
- Thalidomide UK Agency
- Nobody’s Perfect
Senior Correspondent Jones practiced emergency medicine in Southern California for 30 years and now writes for HealthWorldNet.com. He has also published several scientific papers as well as his novel A Murder in West Covina, Chronicle of the Finch-Tregoff case.