The Thalidomide Tragedy Revisited: Mistakes Made and Lessons Learned
January 6, 2015
Though most millennials may not be familiar with the scourge of thalidomide, those involved in the health and life sciences cannot afford to forget the thousands of horrific birth defects this drug caused and the lessons the scientific community learned from the fallout. Regulatory boards, pharma, biotech, and investigators looking to begin clinical trials please take note: we can never make another mistake like this one. The reverberations caused by the thalidomide tragedy are still of deep concern, acutely to the surviving victims, handicapped by severe birth defects, and as a reminder of the pleomorphic relationship between the FDA (and other drug approval agencies) and pharmaceutical companies. The thalidomide tragedy demonstrates the major flaws in pre-modern clinical safety, and proved to be a catalyst to spur essential improvements to a system that was insufficient at protecting patients.
Testing of thalidomide was administered to a range of patients with a range of disorders. However, only one known trial was conducted in pregnant women .Thalidomide quickly became a popular drug that was chemically similar to barbiturates with relatively low known toxicity in adults. During the mid 1950’s the addictive profile of many barbiturates were discovered and paired with a strong correlation to physical dependence. Thalidomide was seen as a novel and safe replacement for barbiturates.
Physicians quickly began to recognize thalidomide’s potential sedative and anti-nausea effects for use in morning sickness. Thalidomide was advertised as a drug, “completely safe for everyone, including mother and child.” The off-label clinical application for treatment of morning sickness was originally advocated by the Australian obstetrician Dr. William McBride. A worldwide trend developed, and it was not until 1961 that detrimental developmental effects on newborn babies was linked to the drug.
Thalidomide has been directly linked to severe birth defects in more than 10,000 babies the world over. Thalidomide quickly became renowned as a notorious killer and disabler of newborns. Those who survived were afflicted with peripheral neuritis, startling birth malformations, missing limbs, deafness, blindness, internal disabilities and organ failure, phocomelia and other congenital effects. This tragedy remains one of the most significant disasters related to prescribed drugs, and has left a lasting scar on the pharmaceutical industry.
The thalidomide tragedy was extensively mitigated by the scrupulous work of the FDA’s Dr. Frances Kelsey. Kelsey, unconvinced by the trial evidence, did not approve thalidomide for use in America, even though it was beginning to be widely prescribed in Europe. Dr. Kelsey exemplified the qualifications necessary to objectively and critically examine clinical data and make informed decisions on drug safety and approval. Further, approval by recognized authorities in one location should not, and does not immediately qualify approval in another. Each individual regulatory agency must thoroughly review clinical data and render it’s own decision on approving drugs. Though redundant, multiple reviews ensure safety and can reveal data that had been previously missed by a different review board. Communication between agencies is also essential, sharing opinions and analysis so that the right decisions can be made. However, varying standards and opinions do exist, and even in modern medicine it is not unusual to have certain drugs approved in one country and illegal in another.
Following the deaths and crippling disabilities attributed to thalidomide the American congress enacted the Kefauver-Harris amendment to the Federal Food, Drug and Cosmetic Act. Now drug companies had to not only prove the safety of their compounds, but the efficacy too. Stricter thresholds of approval based on higher levels of scientific evidence were mandated. Companies had to monitor postmarket safety profiles of their products and adhere to higher manufacturing standards.
It is easy to think of regulatory agencies as a roadblock impeding the development of better drugs and new treatments for diseases. However, the thalidomide tragedy must serve as a reminder for the necessity of regulation in the life sciences, especially when our most vulnerable stand to be effected. Regulation undoubtedly makes the drug discovery process more expansive, a fact that pharmaceutical companies are constantly pushing back against. A balance must be struck between streamlining the trial process to ensure drug discovery can happen efficiently, while at the same time not sacrificing the safety of those enrolled in trials and future patients.
Mellin, G., Katzenstein, M. (1962). “The saga of thalidomide. Neuropathy to embryopathy, with case reports of congenital anomalies.” The New England journal of medicine 267
Franks, M.E., Macpherson, G.R., Figg, W.D. (2004). “Thalidomide.” The Lancet 363:1802-1811.
Barron, D., Dundee, J. (1967). “Clinical studies of induction agents. XVII. Relationship between dosage and side effects of intravenous barbiturates.” British journal of anaesthesia 39: 24-30.
Fadel, D., Serra, H. (2012). “Thalidomide and its legacy, the rational inside the irrational.” Vertex (Buenos Aires, Argentina) 23(104): 245-251.
Kim, J., Scialli, A. (2011). “Thalidomide: the tragedy of birth defects and the effective treatment of disease.” Toxicological sciences an official journal of the Society of Toxicology 122: 1-6.