Editorial Line

The Development of Thalidomide

Swiss pharmaceutical company ‘Ciba’ was the first organisation to commercialise thalidomide in 1953 (Hashimoto, 2002). This same company quickly lost interest in the drug for its apparent lack of diverse pharmacological applications, meaning German company ‘Chemie Grünenthal’ was able to market thalidomide as an epilepsy medication in 1954 (ibid). In finding the drug ineffective in treating this disease, thalidomide was later marketed by Wilhelm Kunz and associates in 1956 as an analgesic sleep-promoter also able to combat first-trimester morning sickness nausea safely (Klausner, Freedman, & Kaplan, 1996).

Animal trials suggested a lack of the compound’s toxicity, while its chemical structure, similar to sleeping medications marketed at the time, led developers to believe thalidomide was harmless and thus fit for for consumption (Teo, 2005). 14 pharmaceutical companies operating in over 40 countries were propagating the drug by the close of the 1950s; only certain countries such as the United States had the lucky insight to delay thalidomide’s effects through the Food and Drug Administration’s lagging approval process (Hashimoto, 2002).

This drug was subsequently distributed across Europe, Australia and Canada, though in November 1961 was retracted from sales due to reports of foetal abnormalities (Klausner, Freedman, & Kaplan, 1996). An estimated 10,000 cases across 46 countries were reported, exhibiting congenital defects of the heart, kidney, ears and eyes as well as limb deformities (Zhou, Wang, Hseih, Wu, & Wu, 2013).

Today, thalidomide is manufactured as THALIDOMID under licence by the American drug company Celgene, who supply thalidomide to patients and clinical trial researchers (Hashimoto, 2002).

The Uses of Thalidomide: Both Intended and Otherwise

The Celgene Drug Safety team asserts the following contraindications: that the drug should not be used where hypersensitivity to thalidomide is known, in patients 12 years or younger, in pregnant or breastfeeding women, and those not willing to employ contraceptive measures who are fertile and fit to procreate (Celgene, 2016). Thalidomide is a known human teratogen, meaning it causes birth defects and thus should never be administered during pregnancy, especially during the 35 to 50 day critical period of pregnancy (ibid). For this reason, contraception is encouraged to continue for 4 weeks following the patient’s treatment with the drug (ibid).  

Despite its scarred reputation in recent decades, thalidomide brings promise in the treatment of a vast array of inflammatory and auto-immune disorders, including rheumatoid arthritis, lupus, malaria, tuberculosis, acquired immunodeficiency syndrome (AIDs), colon and breast cancers, Crohn’s disease and diabetes (Hashimoto, 2002).

In 1965, Israeli Dr. Jacob Sheskin treated lepromatous leprosy patients with thalidomide, observing a substantial subsiding of symptoms (Klausner, Freedman, & Kaplan, 1996). Skin lesions lessened in severity, while acute inflammation also subsided, leading the World Health Organisation to recommend the drug for leprosy treatment (Teo, 2005).

Recent studies have produced results where a 84.7% reduction in ulceration in Behçet’s Disease sufferers indicates the drug’s validity in treating symptoms of autoimmune disorders (Gardner-Medwin, Smith, & Powell, 1994).

Recent studies similarly suggest thalidomide’s viability for use in treatment of HIV; oral ulceration, disease-related weight loss viremia (viruses in the blood) were all shown to decline following a 28-day trial treatment period (Kunachiwa et al., 1999). Conversely, increased blood plasma and T-cell lymphocyte readings in patients are suggestive of thalidomide’s potential use as an immuno-stimulant (ibid).

Thalidomide’s potential for use in cancer treatment is optimistic; it’s use as an anti-inflammatory and a cancerous cytokine inhibitor suggest its potential for use both in symptomatic relief and disease treatment (Teo, 2005). Its status as an angiogenesis (new blood vessel growth) inhibitor is promising, as this biological mechanism is central to the uncontrolled cell replication so problematic to cancer growth (Zhou, Wang, Hseih, Wu, & Wu, 2013).

Other studies even suggest the drug’s potential for use as a tumour growth suppressant (ibid); thalidomide’s ability to induce cell apoptosis primes it as a powerful treatment in inducing anti-tumour activity in patients with severe myolema (Singhal et al., 1999). Following this study, 10 of the 84 participants with progressive myolema went into complete or nearly-complete remission following a six-week trial, signalling the drug’s efficacy (ibid).  

However, in multiple myolema studies the co-incidence of peripheral neuropathy (nerve damage) and neuritis (peripheral nerve inflammation) has limited the drug’s current use in symptomatic treatment (Mileshkin et al., 2006). Chronic use of the drug may cause irreversible nerve damage, meaning that patients experiencing numbness, tickling or paraesthesia are advised to discontinue treatment immediately (Celgene, 2016). Other side effects potentially reducing thalidomide’s capacity for use throughout the general population include dizziness, seizures, impaired wound healing, dermatological reactions, blurred vision, limb swelling and slowed heart rate (ibid).


Thalidomide's Legacy

To talk about the legacy of thalidomide is ultimately paradoxical. On one hand, we have the clear emergence of more stringent regulations surrounding drug development as a result of the 20^th century scandal. However, on the other, this ‘scandal’ is still today, the living representation of a failure on drug development, for survivors who are still living with the consequences of the drug. 

With hindsight it is always easy to realize mistakes and award blame for a crisis such as Thalidomide. For the most part, the liability of the 20^th century disaster rests on the pharmaceutical company, Chemie Grünenthal, for their severe lack of proficient animal testing, before the drug was made accessible to the general population (Stone, 2008). However, lack of proper after drug market surveillance through both the government and hospitals could have also lessened the impact of this drug on families (Stone, 2008). Thus, thalidomide was a landmark case in the evolution of drug trials and testing, and although there are key players and events in this story, which could have potentially been avoided, most likely potential subsequent drug disasters have been avoided as a result. 

The USA is a world leader in many aspects of society, one of them being their well-known Food and Drug Administration (FDA). Following the discovery of thalidomide’s teratogenic effects, in 1962 President John F. Kenney brought in new legislation to the FDA ensuring that “consumers will not be the victims of unsafe and ineffective medications” (FDAgov, 2015). Known as the Kefauver- Harris Amendments after the congressmen who proposed them, these changes in law included requirements of manufacturers to prove effectiveness and sufficient evidence based clinical trials proving safety, of new drugs (FDAgov, 2015). 

President John F. Kennedy, and Dr. Francis Kelsey being honoured in 1962, the same year as the drug law amendments. Kelsey is responsible for Thalidomide never legally entering the drug market in the USA. (Bernstein & Sullivan, 2015)

          In the wake of thalidomide, we see the positive of preventions put in place to prevent another similar and disastrous drug related occurrence, however the scale of such a precedent case delineates that half a century after the event, people are still living the incident; uncompensated and with severe health complications (Stone, 2008). It was only in 2012 that in Australia victims were given monetary compensation for their loss and struggle, and again in 2012 when Grünenthal issued their first apology for the damage Thalidomide caused (Madden, 2015).

Melbournian Lyn Rowe, who won her case against Chemie Grünenthal in 2012 at age 50.

 (Ferber, 2015)

          Despite the length of time for which it has taken 20^th century Thalidomide victims to be given an apology and compensation for the suffering they experience daily as a result, the drug is still being currently used today for the treatment of other disease and sickness (Madden, 2015). A prominent example of Thalidomide’s use today is in Brazil, where although the drug was removed from the market in 1960, it was made available again in 1965 (Crawford, 2015). Approximately 20% of the population in Brazil live below the poverty line, meaning the low quality of housing in which they live is a place for certain diseases to thrive (Crawford, 2015). Leprosy is one of such diseases, and thalidomide has emerged as a drug, which can successfully treat some of its co-morbidities (Vargesson, 2015). However, due to both a lack of education and understanding of the drug, as well as the widespread medication sharing that occurs, many women take Thalidomide today unaware of the risk during pregnancy. Currently more than 100 children have been born with Thalidomide related complications since its re-emergence onto the market in 1965 (Crawford, 2015). Healthcare professionals express the view that the benefits of the drug outweigh the risks.  The national leprosy campaign group leader in Brazil, Artur Custodio likens it to cars, stating, “we don’t talk about banning cars, we say we should teach people how to drive responsibly. It’s the same thing for Thalidomide” (Crawford, 2015). However Thalidomide’s original victims take this as the drug “laughing the in the face of it’s victims”, believing that the drug should have been destroyed in the 1960’s (Harrison, 2001).

          A landmark case in drug reform, Thalidomide was deleterious for the children of its users, however in its wake entered drug trial reform and more stringent management of manufacturers. It can be argued that if it weren’t Thalidomide instigating these changes, another drug would have taken its place. Today, although its existence and use is still problematic in society, it has emerged as a useful drug in treating many human disease (Madden, 2015). For the victims of Thalidomide, nothing can be done to reverse their exposure to the teratogenic drug, however with its continued use more can be done to improve education and understanding of the risks it poses to pregnant women. Perhaps atoning for its past, Thalidomide is making amends through its wide and varied use but it is likely the drug will forever be seen in a tainted light, and a reminder for the necessity of publically safe drug trialling and ethics.

President Kennedy Calls For Stronger Drug Laws (1962)

President Kennedy calls for stronger drug Laws (British Pathe. 1962)

References

Bernstein, A., & Sullivan, P. (2015, August 7). Frances Oldham Kelsey, heroine of thalidomide tragedy, dies at 101. Washington Post. Retrieved from https://www.washingtonpost.com/national/health-science/frances-oldham-kelsey-heroine-of-thalidomide-tragedy-dies-at-101/2015/08/07/ae57335e-c5da-11df-94e1-c5afa35a9e59_story.html

British Pathé. (2014, April 23). President Kennedy Calls For Stronger Drug Laws (1962) [Video file]. Retrieved from https://www.youtube.com/watch?v=2fp5sGvCdVE&feature=youtu.be

Celgene (2016). Production information: THALIDOMID capsules. Retrieved from http://www.celgene.com.au/product-information/

Crawford, A. (2013, July 24). Brazil’s new generation of Thalidomide babies. BBC Magazine. Retrieved 18 October, 2016, from http://www.bbc.com/news/magazine-23418102

FDAgov. (2016). FDAgov. Retrieved 18 October, 2016, from http://www.fda.gov/ForConsumers/ConsumerUpdates/ucm322856.htm

Ferber, S. (2015, December 6). Could thalidomide happen again? Retrieved October 30, 2016, from https://theconversation.com/could-thalidomide-happen-again-46813

Gray, G. (2015, December 7). Why did thalidomide’s makers ignore warnings about their drug? Retrieved October 22, 2016, from https://theconversation.com/why-did-thalidomides-makers-ignore-warnings-about-their-drug-47092

Harrison, G. (2001, January 29). The Legacy of Thalidomide. Retrieved October 07, 2016, from Peterborough Telegraph, http://www.peterboroughtoday.co.uk/news/environment/the-legacy-of-thalidomide-1-107162

Hashimoto, Y. (2002). Structural development of biological response modifiers based on thalidomide. Bioorganic & medicinal chemistry, 10(3), 461-479.

Klausner, J. D., Freedman, V. H., & Kaplan, G. (1996). Thalidomide as an anti-TNF-α inhibitor: implications for clinical use. Clinical immunology and immunopathology, 81(3), 219-223.

Kunachiwa, W., Haslett, P. A., Klausner, J. D., Makonkawkeyoon, S., Moreira, A., Metatratip, P., Boyle, B., ... & Elbeik, T. (1999). Thalidomide stimulates T cell responses and interleukin 12 production in HIV-infected patients. AIDS research and human retroviruses, 15(13), 1169-1179.

Madden, B. (2015, December 8). Why thalidomide survivors have such a tough time getting compensation. Retrieved October 19, 2016, from https://theconversation.com/why-thalidomide-survivors-have-such-a-tough-time-getting-compensation-47164

Mileshkin, L., Stark, R., Day, B., Seymour, J. F., Zeldis, J. B., & Prince, H. M. (2006). Development of neuropathy in patients with myeloma treated with thalidomide: patterns of occurrence and the role of electrophysiologic monitoring. Journal of Clinical Oncology, 24(27), 4507-4514.

Singhal, S., Mehta, J., Desikan, R., Ayers, D., Roberson, P., Eddlemon, P., ... & Zeldis, J. (1999). Antitumor activity of thalidomide in refractory multiple myeloma. New England Journal of Medicine, 341(21), 1565-1571.

Stone, J. (2008). From the holocaust to Thalidomide: A Nazi legacy. Retrieved October 22, 2016, from https://blogs.scientificamerican.com/molecules-to-medicine/from-the-holocaust-to-thalidomide-a-nazi-legacy/

Teo, S. K. (2005). Properties of thalidomide and its analogues: implications for anticancer therapy. The AAPS journal, 7(1), E14-E19.

Thalidomideca. (2016). Thalidomideca. Retrieved 21 October, 2016, from http://www.thalidomide.ca/recognition-of-thalidomide-defects/

Vargesson, N. (2015, December 10). Thalidomide: The drug with a dark side but an enigmatic future. Retrieved October 19, 2016, from https://theconversation.com/thalidomide-the-drug-with-a-dark-side-but-an-enigmatic-future-50330

Zhou, S., Wang, F., Hsieh, T. C., M Wu, J., & Wu, E. (2013). Thalidomide–a notorious sedative to a wonder anticancer drug. Current medicinal chemistry, 20(33), 4102-4108.