A preventable tragedy that changed drug approval forever

Thalidomide’s period of use may have been short but its ramifications have lasted decades, both for people who suffer deformities from its effects and how we now regulate medicines.

Like many ‘wonder drugs’ of the 20th century, thalidomide was first synthesised by the German pharmaceutical industry, in this case Chemie Grünenthal. Experiments to develop a new antibiotic resulted instead in the synthesis of thalidomide, which was seen as a potential safe alternative to barbiturates.¹ Starting in 1957, it was marketed as Contergan, as a treatment for nausea, sleeplessness and anxiety.²

In action

Thalidomide’s action is complex, with it exhibiting traits of an anti-inflammatory as well as an immunomodulatory agent, restricting or promoting protein degradation depending on the cell type.

However, it was also found to have teratogenic effects, most acutely during the 20-36 day period of development, inhibiting the creation of new blood cells,⁴ but the exact method by which this occurs is still unclear.⁶

Removed from shelves

Thalidomide was approved for sale in a variety of countries following approval in Germany; the UK approved it in 1958, with Australia following in 1960, where it was marketed as Distaval. But even as it was starting to be marketed widely, adverse side-effects were being noticed.

In Germany, an employee from the Grünenthal company who had given his wife thalidomide had a daughter born without ears in 1956, while in the UK and Australia the first complaints diagnosed were nerve damage.¹ The link to foetal abnormalities was first raised with Grünenthal in mid-November 1961, when the employee demanded they stop selling the drug, and within days health authorities had removed thalidomide from shelves.⁵

Effects in Australia

Australia’s Dr William McBride, a gynaecologist at the Crown Street Women’s Hospital, was the next to highlight foetal abnormalities in a letter to The Lancet in 1961, where he asked if colleagues had noticed deformities in infants born by women who were prescribed thalidomide during pregnancy.

Following the removal from sale in Germany, and McBride’s letter, thalidomide was withdrawn from sale in Australia, the UK and several other markets.⁴

In the wake of the thalidomide scandal, many countries established government departments to ensure medicines were properly and thoroughly tested before being marketed.⁴ In Australia, the regulatory response was the establishment of the Australian Drug Evaluation Committee, to monitor the safety of new medicines and investigate existing ones.⁴

After ongoing research into other therapeutic uses for thalidomide, it re-entered use in Australia in 2001, and is currently used in the treatment of multiple myeloma, erythema nodosum leprosum and tuberculosis, as well as in numerous off-label treatments.

References

1 Aronson JK. Meyler’s Side Effects of Drugs: The International Encyclopedia of Adverse Drug Reactions and Interactions. 2015:16;795-797.

2 Fifty years of independent expert advice on prescription medicines. Therapeutic Goods Administration (TGA). At: https://www.tga.gov.au/book/fifty-years-independent-expert-advice-prescription-medicines-02.

3 Thalidomide. Drugbank. At: https://www.drugbank.ca/drugs/DB01041.

4 Vargesson N. Thalidomide‐induced teratogenesis: History and mechanisms. Embryo Today: Reviews. 2015:105(2)140-156. https://onlinelibrary.wiley.com/doi/full/10.1002/bdrc.21096.

5 Widerkund, L. The History of Thalidomide [Internet] Lecture delivered at the 1992 United International Thalidomide Congress. At: https://www.thalidomide.ca/wp-content/uploads/2017/12/Dr-Lenz-history-of-thalidomide-1992.pdf.

6 McBride WG. Thalidomide and Congenital Abnormalities. The Lancet. 1961:(278)7216;1358

7 Fintel B, Samaras, AT, Carias E. The Thalidomide Tragedy: Lessons for Drug Safety and Regulation. Helix Magazine. Northwestern University Office for Research. July 2009.