Thalidomide was a sedative drug that was withdrawn in 1961 after being linked to severe birth defects in thousands of babies. It was never tested in pregnant animals before being used in humans. The thalidomide tragedy led to major reforms in drug safety regulations, including the establishment of the FDA and new preclinical testing requirements. It showed the need for rigorous safety testing and established windows of exposure during pregnancy that can cause defects from drug exposure.

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Sixty years on: The thalidomide tragedy
Prepared by: Amit Mishra
Submitted to: Dr. Sayantan Mukhopadhyay
Dev Bhoomi Institute of Pharmacy and Research, Dehradun
(Uttarakhand)
• Correspondence to Author Amit Mishra E-mail: amitmishrapci@gmail.com
Introduction
1.Sixty years ago (2 December 1961) the sedative drug thalidomide was withdrawn
from use in the UK. After being on the market for five years as a treatment for
morning sickness in pregnant women, it had finally been established that the
medicine was responsible for babies being born with underdeveloped arms and
legs and other malformations.
2.No drug has had a greater effect than thalidomide on the extent and intensity of
the preclinical investigation of potential medicines required by the regulatory
authorities. Indeed, the establishment of thalidomide as the cause of the apparent
epidemic of children born with horrific deformities in the late 1950s was
responsible for the institution of some regulatory bodies, such as the United
Kingdom’s Committee on the Safety of Drugs, and for the strengthening of others,
such as the Food and Drugs Administration (FDA) of the United States. Despite
this, the history of the development of thalidomide, and of the subsequent studies
of the teratogenic and other effects of the drug, has become confused, because of
misrepresentation by those anxious to discredit the contribution of animal
experimentation to medical advances.
Thalidomide was never administered to pregnant animals before it was used in
humans.
Laboratory Studies
3.The first paper describing the pharmacological actions of thalidomide was
published in 1956 by Kunz, Keller and Mückter from the Research Laboratories of

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the German pharmaceutical firm Chemie Grünenthal .Thalidomide, designated
then as K17, was alleged to reduce spontaneous movement in mice without the
initial excitement phase observed with other sedative drugs such as phenobarbitone
and glutethimide.
Thalidomide was claimed to be virtually non-toxic, oral doses in excess of
5000mg/kg failing to cause death, whereas 600mg/kg and 300mg/kg doses of
glutethimide and phenobarbitone respectively were sufficient to kill half of the
mice in a test group. Chronic administration of 100-500mg/kg thalidomide to mice,
rats, guinea pigs and rabbits for 30 days appeared to be well-tolerated. Thus it was
proposed by the researchers at Chemie Grünenthal that thalidomide would be a
useful sedative or hypnotic that did not carry the suicide risk of contemporary
medicines.
4.The actions of thalidomide were also investigated by G. B. Somers chief
pharmacologist at the Distillers Company, which was licensed by Grünenthal to
distribute thalidomide in the British and Commonwealth markets. Somers, using
thalidomide as a suspension in 1% carboxymethylcellulose, generally confirmed
the inhibition of spontaneous movement by the drug in mice and also remarked on
its apparent lack of toxicity in animals. Important caveat when discussing the
results of his toxicity studies: “It may well be that the absence of toxicity is due to
a limited absorption, for the compound has a low solubility in body fluids, and
when administered parenterally remains at the site of injection. In the absence of a
suitable assay method absorption studies have not yet been made.”
WINDOWS OF EXPOSURE
5.‘‘All substances are poisons; there is none which is not a poison. The right dose
differentiates a poison from a remedy.’’
A timetable of critical exposure periods for thalidomide embryopathy. For
example, the window of exposure in humans for upper limb malformations is days
24–32 postfertilization; the window for lower limb malformations is days 27–34
postfertilization (Miller and Stro¨mland, 1999). Other endpoints include external
ear malformations (days 20–24), inner ear malformations (days 24–34), thumb
hypoplasia (days 21–28), and triphalangism of the thumbs (days 32–36). The
sensitive period during pregnancy for thalidomide effects in humans is
approximately days 20–34 after fertilization (Miller and Stro¨mland, 1999; Miller
et al., 2009). A summary of these windows of critical exposures and limb defects.

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Defects of Thalidomide Children
• 6 Defects of the Upper Limbs.
• Defects of the Lower Limbs
• Defects of the Ears and Eyes.
• Defects of Internal Organs

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7.The malformations induced by thalidomide were rare under normal conditions,
consisting of limb dysmelia in 80% and ear defects in 20%.326 The drug was said
to increase the rate of limb reduction by 80-f0ld;~~’ the most common pattern of
malformation, encountered in 38% of the cases, was upper limb amelia or
phocomelia, with normal legs.328 Other malformations occurring in addition to
limb and ear defects included, in descending order of frequency: loss of hearing,
abducens paralysis, facial paralysis, cryptorchidism, renal malformations,
congenital heart disease, inguinal hernia, and stenosis/atresia of the anus, pylorus,
or duodenum. 329
The evolution of FDA in shadow of Thalidomide
8.Francis Kelsey, Ph.D., was hired to work for the FDA in 1960 and the first drug
she was asked to review for approval was thalidomide. she was vindicated when
children being born with birth defects were linked back to the use of thalidomide.
From 1956 to 1962, approximately 10,000 children were born with severe
malformities, including phocomelia, because their mothers had taken thalidomide
during pregnancy. she played a key role in shaping and enforcing the 1962
Amendments.

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The Kefauver-Harris Amendment provided the modern scenario for approving new
drugs:
• Initial drug discovery.
• Preclinical (animal) testing.
• An investigational new drug application (IND) outlines what the sponsor of
a new drug proposes for human testing in clinical trials.
• Phase 1 studies (typically involves 20 to 100 healthy people).
• Phase 2 studies (typically involves 100 to 500 people with the ailment that
the new drug is intended to treat).
• Phase 3 studies (typically involves 1,000 to 5,000 people with the ailment
that the new drug is intended to treat).
• The pre-NDA period, just before a new drug application (NDA) is
submitted. A common time for the FDA and drug sponsors to meet.
• Submission of an NDA is the formal step asking the FDA to consider a drug
for marketing approval.
• After an NDA is received, the FDA has 60 days to decide whether to file it
so it can be reviewed.
• If the FDA files the NDA, an FDA review team is assigned to evaluate the
sponsor's research on the drug's safety and effectiveness. This review may
take from 6 months to 2 years.

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• The FDA reviews information that goes on a drug's professional labeling
(information on how to use the drug).
• The FDA inspects the facilities where the drug will be manufactured as part
of the approval process.
• FDA reviewers will approve the application or find it either "approvable" or
"not approvable."
• Post marketing study commitments, also called Phase 4 commitments.
9.After thalidomide babies tragedy FDA's attitude was changed and pushed
congress to enact so-called "Kefauver Amendment" to Act in 1962. Senator
Kefauver's motives were noble to bring better , safer , medicine and establish a
more effective system of endorsement of drug laws.
Relation between Thalidomide tragedy & Kefauver-Harris Amendment
10.Senator Estes Kefauver, who sat on the Senate Antitrust and Monopoly
Subcommittee, decided that in dealing with medications, the government must do
more than control their labels, contents, and safety and their marketing and
distribution processes. It must also control their prices and enforce “competition.”
In 1960, Kefauver initiated hearings in an attempt to expose unfair marketing
practices. Kefauver’s bill called for a scheme of compulsory patent sharing. Each
pharmaceutical company would, after three years, be required to share its new
patents with competitors, while collecting an annual royalty fee of some 8 percent
of the total.
In the United States, an NDA for thalidomide had been submitted to the FDA in
1960, but approval had been delayed as the FDA investigated adverse neurological
reactions. FDA officials had not even suspected that the drug caused birth defects.
In 1962, President Kennedy bestowed the Distinguished Federal Civil Service
Award on the FDA physician who held up approval, Frances Kelsey, even though
her withholding of approval was more a matter of bureaucratic delay than of
investigation.

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REFERENCES
1 Schardein, J L and Keller, K A (1989) Potential of human developmental
toxicants and the role of animal testing in their identification and
characterisation. CRC Crit. Rev. Toxicol. pg 251-330
2 Animals and Medicine: The Contribution of Animal Experiments to the
Control of Disease CH18
3 Animals and Medicine: The Contribution of Animal Experiments to the
Control of Disease CH18
4 Somers, G F (1960) Pharmacological properties of thalidomide (α-
phthalimido glutarimide), a new sedative hypnotic drug. Brit.
J. Pharmacol. 15 111-16.
5 James H. Kim*,1 and Anthony R. Scialli†Thalidomide: The Tragedy of
Birth Defects and the Effective Treatment of Disease pg 2
6 R. W. SMITHELLS Defects and Disabilities of Thalidomide Children
British Medical Journal, 1973, pg 269-72
7 James L. Schardein Kit A. Keller POTENTIAL HUMAN
DEVELOPMENTAL TOXICANTS AND THE ROLE OF ANIMAL
TESTING IN THEIR IDENTIFICATION AND CHARACTERIZATION
pg 275
8 http://rx-wiki.org/index.php?title=Kefauver-Harris_Amendment
9 The Real Thalidomide baby 1960-1977 ( 1997 Third Year Paper) (DASH)
10 https://www.fdareview.org/issues/history-of-federal-regulation-1902-
present/#p10.