The Thalidomide Tragedy and its Effect on Drug Safety Regulations

Swiss pharmaceutical company Ciba first synthesized thalidomide, a sedative similar to barbiturates, in 1953. The company’s intention was to use it as an anticonvulsant; however, since no such success was seen in tested lab animals, the company stopped its research on the drug. In October 1957, West German company Chemie Grünenthal found that thalidomide aided sleep, with no apparent side effects or maximum dose, and so it became a popular sleeping pill (as Contergan) in West Germany. Doctors used thalidomide, in combination with aspirin, to treat a range of illnesses, from colds and coughs to asthma and anxiety.
Some researches around this time showed that thalidomide relieved morning sickness in expectant women, and soon this off-label use was being recommended during pregnancy in 48 countries. Then, in 1960, some German medical journals reported cases of peripheral neuritis associated with long-term use of thalidomide. In 1961, based on questionnaires sent to parents of deformed infants, and their physicians, and noticing that about 20% of the mothers had taken thalidomide, a German pediatrician, Widukind Lenz, hypothesized that prenatal exposure to thalidomide could cause severe deformities in newborns. In late 1961, he reported his findings to Chemie Grünenthal.
Similarly, around the same time, an Australian obstetrician, William McBride, also observed severe birth defects in the babies whose mothers had taken thalidomide. These included dysmelia (shortened, absent, or extra arms or legs), bone hypoplasticity (incomplete development of extremities), and ear, heart, and internal organ defects. He reported his findings to the Scotland-based Distillers Company Limited Laboratories, which produced thalidomide for the UK. Within a few years of its launch, more than 10,000 babies worldwide were born with birth defects due to thalidomide use, and by early 1962, it was banned in many countries.
Fortunately, in the USA, an FDA inspector, Frances Kelsey, had prevented the drug’s approval because of incomplete and insufficient data on its safety and effectiveness, and no data on whether the drug could cross the placenta, which provides the developing fetus with nourishment. And, there were no results yet available from U.S. clinical trials of the drug. At the time, clinical trials were not fully reliable, since they did not require FDA approval and were not subject to oversight. The thalidomide tragedy led the US Congress to pass the 1962 Kefauver-Harris Amendments to the 1938 Food, Drug, and Cosmetic Act, which imposed severe guidelines for the process of drug approval.
It required that any sponsor company that planned to investigate that drug clinically had to provide the FDA with a detailed outline of the study, including information concerning preclinical studies, the number and qualifications of the clinical investigators, and the nature of the study. The sponsor company had to monitor the progress of the studies and continually report its findings to the FDA, and clinical investigators had to sign contracts agreeing to keep adequate records of receipts of drugs and name of persons to whom the drugs were given. The FDA also created pregnancy categories; a ranking of drugs based on their effects on reproduction and pregnancy.
Before the 1962 Amendments, there were few federal regulations for approval or monitoring of clinical trials, and no laws that required doctors to keep records of prescribed drugs; neither were they required to follow-up with their patients. The 1962 Amendments required that drug manufacturers prove not only the safety, but also the efficacy of the drugs. The Amendments also mandated that the FDA had to approve a new drug application before the developing company could publicize the product. Before that, if the FDA did not disapprove a drug application within six months, then the drug would be automatically approved within the subsequent 60 days. Currently, it can take anywhere from eight to twelve years to get approval for a new drug, and involves animal testing and tightly regulated human clinical trials