Thalidomide is a drug that was produced by the German company Grünenthal in the early 1950’s. Upon release it was marketed for morning sickness and nausea but became known as a wonder drug that treated many illnesses. This was until it was found to cause severe birth defects, mostly the malformation of limbs, and was subsequently banned in most countries. This demonstrated the need for stricker guidelines and testing before a drug can be approved, which did happen as a direct result of this scandal. More recently thalidomide has been found to be a very effective treatment for cancer and leprocy but due to it’s past and the damage it can cause, further use must and will be taken with extreme precaution.

Timeline

1953 – Thalidomide is created in Germany by the Grünenthal Group¹.

1955 – Animal testing of the drug led them to believe it was safe as they couldn’t harm the test subjects no matter how high the thalidomide dosage².

1956 – The first known thalidomide baby is born to a Grünenthal employee, although at the time the cause was not recognised.

1957 – The drug becomes available over-the-counter in West Germany. Marketed as a safe sedative and was widely used for morning sickness and nausea.

1958 – Thalidomide becomes available in the UK, renamed Distaval it was marketed specifically to pregnant women.

1959-1961 – Many reports of thalidomide causing nerve damage, most notably Dr Florence in The British Medical Journal. This causes Grünenthal to apply for a prescription only status, and also add labels to the bottles warning of nerve damage, although no further testing was conducted.

1960 – Thalidomide is launched in Australia and New Zealand while at the same time being refused Federal Drug Agency (FDA) approval by Frances Oldham Kelsey, who was not satisfied by the level of testing the drug had received. Her rightful reluctance to approve this drug led to potentially thousands of children being born healthy that otherwise would not have.

1961 – The companies selling thalidomide, especially Grünenthal, received more and more complaints and concerns about the nerve damage it causes and now the malformation of limbs of newborns. Totalling approximately 900 from doctors and pharmacists. This included Australian doctor William McBride who published in the Lancet Medical Journal the connection he found between deformed babies and mothers who had taken thalidomide.

1961 – These reports and the media attention they got caused thalidomide to be taken off the market in Germany, UK and Australia. Although it was not banned in other countries until the following year.

1962 – To prevent the events of this scandal from ever reoccurring the US made amendments to its Federal Food, Drug and Cosmetics act. This set a much higher testing standard and made the marketing of new drugs also need FDA approval.

1964 – First signs that thalidomide can be effective against leprosy by Jacob Sheskin in Jerusalem³.

1967-1970 – The trials convicting nine Grünenthal employees of negligent manslaughter and for compensation of the families take place. This results in the families being forced to settle and Grünenthal paying out 100 million marks, with the government adding a further 100 million.

1972 – The UK trials lasted longer than the German trials, ending in 1972 and resulting in 32.5 million pound compensation.

1998 – Thalidomide is approved by the FDA for use against leprosy, although this time it was treated much more carefully. It was not perfect though as the warning labels were misunderstood by countries like Brazil and some thalidomide babies were still born. These families were much later (2009) compensated by the Brazilian government.

2007 – Thalidomide is found to effectively treat bone marrow cancer patients. And so was allowed to be used on patients multiple myeloma and other similar conditions.

2012 – Grünenthal releases a statement apologising for the consequences of the drug, but was criticized for it not being a sincere apology not coming soon enough. They stated that the silence should be taken “as a sign of the silent shock your fate has caused us”⁴.

Lit Review

Thalidomide was first marketed in West Germany in the year 1957 by the company Grunenthal, after tests had been run on animal and human models, Initially, the drug claimed to cure ‘anxiety, insomnia, tension’, and most significantly to alleviate morning sickness in pregnant women⁵. The first reports to flag thalidomide as causing birth defects were made by McBride and Lenz in British medical journal The Lancet in 1961.

Many current scientific commentators condemn the way in which animals were used in the testing process. UK organisation Understanding Animal Research did not condemn the use of animals in early testing of thalidomide, but instead stated that the testing methods were incomplete. Had the drug been tested on pregnant animals, ‘the same birth defects would have shown up in the animals’, and the drug would have been flagged as causing a threat to pregnant women⁶. Other critics, such as toxicologist Dr. Shayne Cox Gad, also did not blame animal testing for the safety failures, stating that the animal testing procedures used in the United States at the time would have ‘’identified the hazard’, and ‘prevented the tragedy’⁷, and criticises the methods used by Grunenthal for the failure.Some particular sources, however, claim that animal testing did occur during the initial stages of thalidomide testing. Nobel winning chemist Roald Hoffman stated that by the late 1950s teratogenicity testing (testing new drugs’ effect on pregnant animals) was routine in major pharmaceutical companies⁸. Certain periodicals, including the Times of London and German medical journals stated that teratogenicity testing did occur in the initial states of thalidomide testing⁹.

After the scandal broke, Sulamaa and Ryoppy, Finnish medical experts, noted in The Lancet that prior to the Thalidomide incident, congenital bone defects were uncommon¹⁰. In regards to treatment, the medics considered that attempting to implement artificial limbs was ‘a poor solution’¹¹, and found that operations attempting to reconnect the bones of affected limbs back to the central skeletal structure was the most effective method, with ‘muscular power gradually increasing’ and overall appearance improving. Marjorie Wallace, founder of the “Sane” Foundation, labeled the impact of thalidomide as ‘a cruel lottery’, describing how most mothers did not have children who were affected by thalidomide, since the drug was most devastating if taken 20-40 days after conception¹². Other sources argue that Grunenthal attempted to cover up the early signs of Thalidomide’s adverse effects. The authors of one 2012 Newsweek article claim that by 1959, ‘despite the overwhelming evidence’, Grunenthal covered up any default in their new wonderdrug, even ‘bribing doctors’ and ‘pressuring critics’¹³. These claims have been backed up by other such sources, including Elisabeth Cawthon, Legal History doctorate, who claims that Grunenthal had gathered ‘mixed’ results from its initial trials on humans, but that the ‘lucrative market’ prompted the company to pursue the production and distribution of the drug¹⁴.

In her writings for the Salem Press, Cawthon also explores how early recognition of the Thalidomide disaster, as discussed, resulted in the passing of the Kefauver-Harris Amendment, a clause which gave the FDA more power to oversee the passage of internationally tested drugs into the USA. The passing of this law faced ‘potent opposition’¹⁵, however witnesses who testified against the drug’s debilitating effects, both domestically and abroad, managed to get the law passed in July 1962.There is even literature which links the Grunenthal company and the development of Thalidomide to the Nazis, and former Nazi officers who were responsible for developing drugs and antidotes during Hitler’s rule of Germany. For example, Roger Williams writes in Newsweek that ‘former Nazi members were recruited by Grunenthal’ due to their previous ownership of pharmaceutical companies and their abilities in the medical field. This also led to the scandal being even more contentious.

There has even been a documentary film (Attacking the Devil), released in 2014 about the Thalidomide scandal by the Weinstein directorial company, labeling it ‘the Last Nazi War Crime’, and describing the story as ‘incredible’¹⁶, and ‘the world’s most devastating man-made disaster’ aside from wars¹⁷. The documentary features several surviving victims of the thalidomide scandal and their families, giving live testimonies, which has prompted The Guardian to label it ‘rich, complicated, and affective’¹⁸.

How Grunenthal was formed, the Nazi influence (Historical Context)

At the end of World War Two a business owned by Nazi party members Hermann and Alfred Wirzt, which had previously focused on soaps, perfumes and cleaning products found a new direction. In 1946, the Wirtz family formed Grunenthal, a small company that would become a haven for medical professionals looking for work as it developed drugs desperately needed in the war’s aftermath.

Among those invited to the company by Hermann Wirtz, was a large group of leading Nazi scientists who both worked with the SS and in the Nazi extermination centers including Martin Staemmler, a leading proponent of the Nazi “racial hygiene” program. Following Germany’s invasion of Poland, he had worked with the SS on its population policy, deciding who should live and who shouldn’t. At Grunenthal, he was head of pathology at the time thalidomide was being sold. Perhaps the most infamous Grunenthal’s employees was Otto Ambros, who was on the four inventors of the nerve gas used in Nazi extermination camps and was Hitler’s adviser on Chemical warfare. Ambros was the chairman of Grunenthal’s advisory committee when Thalidomide was being developed and was on the board of the company when Contergan was being sold. With such a strong Nazi background, many believe Thalidomide may have been tested on Polish prisoners of the death camps¹⁹.

Ongoing Impact to Medicine

The scandal took place at a time when the Laboratory seemed a world away from regular people. Each drug was advertised as capable of performing miracles and the world believed it. Never had the credibility of Laboratories or medical scientists in general been questioned on such a scale. It is estimated that up to 100,000 cases of deformed birth have been caused by Thalidomide²⁰ and this enormous global reach of the scandal opened the world’s eyes to the drugs they were putting inside their bodies and the potential side effects, changing how society viewed medicine as a whole. No longer would scientists of the Laboratory be trusted purely because of their status. The world became more cautious of what drugs were allowed to be distributed within certain countries and it set a benchmark for medical testing and safety based evidence. The scandal also importantly showed Laboratories and Scientists around the world that they can be held accountable if they do make and error, and the global impact that a mistake can have in a position of power like theirs.

In the United States, Dr Frances Kelsey who, as her first project at the FDA, prevented Thalidomide from entering the country at the time of the scandal based on the lack of safety data and rigorous studies provided by Grunenthal. After the true impact of the drug was discovered, the FDA’s guidelines were re-worked to far higher levels of rigor to prevent something like this from occurring again. These regulations go mostly unchanged to this day²¹.

Thalidomide, now reintroduced to the medical world for other treatments, remains an ongoing reminder of the dangers of misuse of drugs and the importance of communication between the medical profession and society. In Brazil, where Thalidomide is widely used to treat leprosy, Thalidomide babies are still being born to this day²².

Thalidomide became one of the first strong examples of a drug searching for a disease rather than a disease searching for a drug. Scientists knew that Thalidomide has a strong potential to cause a reaction, but applying this reaction for a positive result was the real test. As Thalidomide was proven to treat leprosy, multiple myeloma, tuberculosis, some cancers, HIV/AIDS and Crohn’s disease and more, the scientific world was reminded to not rule anything out of research.

Relationship to Themes outlined in Mind, Body and Medicine

The Thalidomide scandal is a great example of the problem of the disappearing ‘Sick-Man’ as outlined by Jewson²³. In this scandal the true dominance and potential abuse of power held by the Laboratory is put on full display. Society was told by the Lab that Thalidomide was a wonder drug because of its revolutionary safety and effectiveness. Many countries took the bait despite a lack of proper testing from Grunenthal. ‘Sick-Men’ around the world were prescribed this drug by their doctors who were told by the Labs that the drug was safe, and it resulted in tragedy. This made society wake up to the platform of superiority that the Lab had risen to, and the fact that Grunenthal still remains a company today and only compensated for the lives they shattered on one occasion after being taken to court, highlights the untouchable status that the lab has in some situations.

The thalidomide scandal was essentially the catalyst for evidence based medicine. Due to its widespread use and poorly documented trades, the outbreak spread in an uncontrollable and sporadic manner²⁴. This therefore caused a global reaction to the issue and has since affected the ways in which many countries distribute and deal with drug testing now. Regulations regarding the introduction of new medications in the market is now much more rigorous and stringent with what may pass into public consumption. Tests are run in a thorough and succinct manner as opposed to general hearsay which was prevalent before the scandal broke out in the late 1950s²⁵.

The introduction of the Kefauver Harris Amendment by the U.S Federal, Food, Drug and Cosmetics Act (FDA) is one of the more large scale acts which developed in response to the scandal’s outbreak²⁶. The act introduced the requirement of actual proof and evidence regarding the safety and efficacy of the proposed drug before being allowed into the market. Drug manufacturers had to be completely transparent about the side effects and were no longer able to advertise with false information regarding the effectiveness and use of the proposed drug. This has been the current model of drug testing since and has essentially established a system that prevents an outbreak like this from ever happening again.

The United Kingdom reacted in a multitude of ways mostly involving the establishment of different regulatory devices with the overall aim to improve “safety, efficacy [and] quality of medicinal products”²⁷. In response to this many more countries have updated their regulations regarding the testing of new drugs in the market²⁸.

The scandal also brought to light the development of multiple drug testing procedures including the randomised, double-blinded, placebo controlled experiment. The most significant being the double blinded experiment which still remains to be one of the larger benchmarks in drug tests today. Although these tests were not entirely new, being introduced in the early 1940s by the epidemiologist Richard Doll²⁹, the full employment of the tests did not come into use until after the scandal. These tests promoted a justified and controlled experiment, where the outcomes of the experiment could provide convincing evidence of the effects of the tested drug³⁰.

In addition to these tests, medications now had to go through a series of test phases before entering the public market³¹. This included a series of gradually increasing phases from a small controlled group (phase I) to a much larger test group of about 100 to 1000 participants (phase III). The final phase (phase IV) includes the large scale documentation of the adverse effects of the drug in the general population over an extended period of time. Participants are to be educated of the potential side effects and must remain closely monitored throughout the experiment process. This ensures that if ever an outbreak occurs, it would be in a controlled environment limited to a known and selected few individuals. The documentation process is therefore lightened and much more efficient.

In response to the large and unquantifiable figures related to the amount of affected patients, the issue of pregnancy termination was also on the rise³². This is an issue that is still ongoing in modern bioethics although the current jurisdiction has skewed slightly in recent years with the possibilities of prenatal testing^{33 34}. This brought up the importance of education towards proper drug use, with stronger medications being required to pass through a doctor before reaching the patient. A short counselling session would have to be completed to inform the patient of the potential side effects and what must be avoided during the medication period.

In current times, thalidomide is still being used as a treatment for more serious diseases such as leprosy and HIV/AIDS³⁵. The prescription procedure currently is much more stringent and controlled as opposed to its earlier spread. The use of thalidomide is seen as a last resort type of use, with patients being required to be fully aware of the consequences of undergoing this treatment with the full disclosure of avoiding pregnancy. The actual uses of thalidomide, however, weren’t discovered until after the scandal broke out and just after the withdrawal of thalidomide from the market. The positive effects of the drug were brought up during the HIV/AIDS epidemic which included experimentations of different withdrawn medications³⁶. Celgene is one of the recent corporations which deals with the trade of thalidomide as a treatment for certain cancer types³⁷. Celgene has employed a risk management program which aims to reduce the amount of affected patients who are pregnant during their medicated state. The program achieves this by requiring a patient examination and registration which highlights the prevention of pregnancy. The program has proved to be effective as there has been no recorded affected births in the U.S since.

In conclusion, the thalidomide scandal has managed to force the employment of more stringent control measures and has brought to light a number of drug trials which define the ways in which drugs are tested and distributed in current times.

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References

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10. The Lancet, 1 (1960): 130.
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14. Elisabeth Cawthon, “Thalidomide Tragedy Prompts Passage of the Kefauver-Harris Amendment”, in Salem Press Encyclopedia (2015).
15. Ibid.
16. “Thalidomide Scandal goes to Hollywood”, Sunday Times, November 15, 2015.
17. Martin Fletcher, “The Thalidomide Scandal”, THe Daily Telegraph, September 1, 2016.
18. “Spotlight isn’t bad”, The Guardian, February 1, 2016.
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33. ZabidiAzhar Mohd Hussin et al., “Permissibility Of Prenatal Diagnosis And Abortion For Fetuses With Severe Genetic Disorder: Type 1 Spinal Muscular Atrophy”, Annals Of Saudi Medicine 30, no. 6 (2010): 427, doi:10.4103/0256-4947.72259.
34. Harry Harris, Prenatal Diagnosis And Selective Abortion (Cambridge, Mass.: Harvard University Press, 1975).
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36. “Could Thalidomide Happen Again?”, The Conversation, 2016, http://theconversation.com/could-thalidomide-happen-again-46813.
37. “Risk Evaluation And Mitigation Strategy Program”, Celgene, 2016, https://www.celgeneriskmanagement.com/REMSPortal/rems/portal/REMSPortal.portal.