Could the thalidomide tragedy have been averted by more extensive animal testing?
Thalidomide is similar in structure to two sedatives introduced in Germany in the early 1950s – diazepam, better known as Valium, and barbital. Because of the similarity, a German company called Chemie Grünenthal first manufactured and sold thalidomide as a sedative in 1957. Chemie Grünenthal tested thalidomide on pregnant women in countries other than Germany and saw no problems – none in the first trimester of their pregnancy that is. Testing thalidomide on people in other countries was unethical but not surprising since the medical director at Grünenthal, Heinrich Mückter, had been involved in experiments on civilians at Krakow, for the Nazis during WWII (Dark Remedy: The Impact of Thalidomide and its Revival as a Vital Medicine by Trent Stephens & Rock Brynner. Perseus: 2001). In light of this, to think they did not test on pregnant animals is implausible.
When reports of birth defects from thalidomide began appearing, Grünenthal stepped up advertising campaigns and threatened physicians who reported that thalidomide was dangerous. After thousands of malformed human babies were born, and after researchers had failed to produce similar malformations in numerous other species, they finally found that an obscure breed, the White New Zealand rabbit, also gave birth to malformed offspring, but only at a dose between 25 to 300 times that given to humans. Eventually some monkeys gave birth to deformed offspring too, but it took ten times the normal dose to make this happen. (Exp Mol Path Supl, 1963;2:81-106; Federation Proceedings, 1967;26:1131-6; Teratogenesis, Carcinogenesis, and Mutagenesis 1982;2:361-74)
Vested-interest groups such as the Research Defence Society perpetuate the myth that the United States government did not approve thalidomide because animal tests had raised suspicions about the drug. The facts are different. Frances Kelsey, a medical officer at the FDA stated the decision not to allow thalidomide was based on the fact that it led to peripheral neuritis, numb and tingling fingers in adult humans (The Scientist January 22, 2001 p14). Animal tests had nothing to do with the decision.
Was thalidomide tested on pregnant animals before marketing? In all likelihood, yes (see Dark Remedy: The Impact of Thalidomide and its Revival as a Vital Medicine by Trent Stephens & Rock Brynner. Perseus: 2001). Specific teratogenicity testing may or may not have been done, but general animal tests certainly were. Roald Hoffmann writes;
“Indeed animal testing for teratogenicity of new drugs was routine in the major pharmaceutical companies. Hoffmann-LaRoche’s Roche Laboratories published a major reproductive-system study of its Librium in 1959. Wallace Laboratories did so for Miltown in 1954. Both incidents antedate the thalidomide story.” (Roald Hoffmann, The Same And Not The Same, Columbia University Press 1995 p136)
In light of this, it would be unusual for some of the animal tests not to have been for teratogenicity. Even Time magazine February 23, 1962, stated that thalidomide was released “after three years of animal tests.”
The bottom line is this: more animal testing would not have prevented the release of thalidomide, because scientists would not have found the side effects. Even if they had tested the White New Zealand rabbit, thalidomide would have still come to market since the vast majority of species showed no ill effect from the drug. The following is a small fraction of the many quotes from scientists and scientific journals which verify this fact:
“There is at present no hard evidence to show the value of more extensive and more prolonged laboratory testing as a method of reducing eventual risk in human patients. In other words the predictive value of studies carried out in animals is uncertain. The statutory bodies such as the Committee on Safety of Medicines that require these tests do so largely as an act of faith rather than on hard scientific grounds. With thalidomide, for example, it is only possible to produce specific deformities in a very small number of species of animal. In this particular case, therefore, it is unlikely that specific tests in pregnant animals would have given the necessary warning: the right species would probably never have been used.” ( Professor George Teeling-Smith, in A Question of Balance; the benefits and risks of pharmaceutical innovation, p 29, publ. Office of Health Economics, 1980)
“…rats are refractory to thalidomide-induced teratogenesis” (Neurotoxicol Teratol. 2001 May-Jun;23(3):255-64. Neurobehavioral teratogenic effects of thalidomide in rats. Vorhees CV, Weisenburger WP, Minck DR)
“We chose a dose of thalidomide close to the estimated amount required to produce human anomalies. This dose had no detectable toxic effects in the monkey” (Science 1963;139:1294-95)
“Grünenthal has tried to reproduce phocomelia in rats, mice, and rabbits and has failed, In Keil the drug was fed to hens and the chicks were normal.” (Helen Taussig, Journal of the American Medical Association, June 30, 1962: A Study of the German Outbreak of Phocomelia: The Thalidomide Syndrome)
“Numerous attempts to reproduce the malformations which occured in human babies from Thalidomide-treated mothers have met with only limited success. Although many representatives of aves [birds] and mammalian experimental species have been investigated for this purpose, the results fall short of paralleling the effect of the drug on the human foetus.” (Nature 1966;210:958-959)
“The extensive animal reproductive studies to which all new drugs are now subjected are more in ...the nature of a public relations exercise than a serious contribution to drug safety.” (Prof R W Smithells, Monitoring for Drug Safety, ed. Inman, p 306-313, 1980)
“The great majority of perinatal toxicological studies seem to be intended to convey medico-legal protection to the pharmaceutical houses and political protection to the official regulatory bodies, rather than produce information that might be of value in human therapeutics.” (Prof D F Hawkins, Professor of Obstetric Therapeutics & Gynaecology, Hammersmith Hospital, London, in the book Drugs and Pregnancy: Human Teratogenesis and Related Problems)
“More than 800 chemicals have been defined as teratogens in laboratory animals, but only a few of these, approximately 20, have been shown to be teratogenic in humans. This discrepancy can be attributed to differences in metabolism, sensitivity and exposure time.” (Dr Beat Schmid, Trends in Pharmacological Sciences; 8:133, 1987)
“In approximately 10 strains of rats, 15 strains of mice, 11 breeds of rabbits, 2 breeds of dogs, 3 strains of hamsters, 8 species of primates and in other such varied species as cats, armadillos, guinea pigs, swine and ferrets in which thalidomide has been tested, teratogenic effects have been induced only occasionally.” (Schardein, JL, Drugs as Teratogens, 1976 and Schardein, JL, Chemically Induced Birth Defects, Marcel Dekker 1985)
Next Question |
