The Thalidomide Disaster

Amanda Mortensen

Edited by Ann Vadakkan, Kira Small, Mac Kang, and Roohie Sheikh

Coronary heart disease. Limb deformities. Nerve damage and early onset osteoarthritis. Many scientists deem this 50 mg tablet to be “the biggest man-made medical disaster ever” [1].

The thalidomide tragedy is one of inadequate drug testing and poor regulatory oversight, exposing a pharmaceutical market prioritizing speed and profit over scientific evaluation. It is remembered by its devastating impact on thousands of families across the world. What followed were sweeping reforms in how drugs are tested, approved, and monitored globally. However, questions persist regarding the effectiveness of these measures and whether more can be done to ensure patient safety. 

Thalidomide (C13H10N2O4) was introduced in 1954 by the German company Chemie-Grünenthal following the postwar antibiotic boom. Consisting of two rings and an asymmetrical carbon, Thalidomide exists as two enantiomers (mirror-image molecules): the R-enantiomer and the S-enantiomer. While the R-enantiomer is merely a sedative, the S-enantiomer was later discovered to be teratogenic, or severely disruptive to embryonic development [2]. Thalidomide was manufactured and distributed as a mixture of both forms, which could interconvert in the body, making it impossible to separate the therapeutic effects from the devastating side effects.

The testing protocols employed by Chemie-Grünenthal were grossly inadequate by modern standards. The company conducted minimal animal studies–and when they did, primarily on rodents—which proved insufficient in detecting the drug’s teratogenic effects. No studies were conducted on pregnant animals, and the testing period was too short to identify long-term effects [3]. 

Despite these significant oversights, the company aggressively pursued market approval. Thalidomide was marketed under various names globally–Contergan in Germany, Distavel in the UK, Softenon in Europe, and Kevadon in Canada–which would make it exceptionally difficult to monitor in the coming years [4]. The drug was promoted through an aggressive marketing campaign that emphasized its “complete safety” for all patients, including pregnant women. Marketing materials specifically highlighted its effectiveness against morning sickness and insomnia, leading to widespread prescription to pregnant women–the very population most vulnerable to its teratogenic effects.

The timing of Thalidomide exposure was integral to the severity of its effects. Between 20 and 36 days after fertilization, there is a ‘critical period’ in which rapid embryonic growth, blood vessel formation, and limb development occurs [5]. Thalidomide usage by pregnant women primarily manifested in phocomelia, a condition characterized by severely malformed or absent limbs [6]. Other effects included absent or malformed ears, heart problems, and malformation of internal organs. Even a single dose of Thalidomide during this critical window caused severe birth defects in 50% of pregnancies [7]. 

Initially, Thalidomide sales skyrocketed, with manufacturers reaping substantial profits. However, as reports of side effects kept emerging, these profit-makers struggled to block attempts to withdraw it from the market. Thalidomide was officially removed from global markets in 1961.

The United States was the exception. Thanks to the Food and Drug Administration's (FDA) newly hired medical officer, Dr. Frances Kelsey, Thalidomide was never approved for sale in the United States. Kelsey found deficiencies in all of Thalidomide’s chemical data and insisted that more be collected. Moreover, the correlation between Thalidomide and peripheral neuritis (injury to the brain and spinal cord) was increasingly apparent, leading her to question the drug’s safety in pregnancy [5]. Citing concerns about fetal development, Kelsey resisted intense pressure from the pharmaceutical company to approve the drug, effectively preventing widespread Thalidomide use in the US market. America’s therapeutic safety standards were still far from those that exist today.

This close-call with Thalidomide led to the passage of the 1962 Kefauver-Harris Amendments to the Federal Food, Drug, and Cosmetic Act. These amendments transformed drug regulation in the US, significantly increasing the burden of proof for drug manufacturers [6]. They introduced the concept of informed consent in clinical trials and established strict protocols for drug testing. Animal experiments were no longer considered sufficient; manufacturers were required to conduct regulated human trials to demonstrate both drug efficacy and safety for people [6]. Moreover, the FDA was granted a 180-day time frame to approve or reject new drug applications, a significant extension from the previous 70 days. This aimed to facilitate more careful review of applications and prioritize consumer safety over rapid sales profits [6].

The international response to the Thalidomide disaster was swift and comprehensive. In Germany, where the tragedy originated, the government established the Bundesinstitut für Arzneimittel und Medizinprodukte (BfArM), or the Federal Institute for Drugs and Medical Devices. It created a robust framework for drug and safety approval, requiring manufacturers to undergo rigorous testing procedures before their medicine was advertised to the public. This included the submission of substantial clinical data, packaging information, distribution plans, and risk-benefit assessments prior to entering the drug approval process [7]. A regulatory body like the BfArM had never before existed in Germany, and its impact was obvious: drug approval slowed, side effect monitoring increased, and the public gradually grew to trust their medical regulatory system. Today, the institute continues to prioritize transparency in drug approval processes, protecting the public from another Thalidomide-like tragedy. 

As for Chemie-Grünenthal, the company faced numerous class action lawsuits for alleged negligence and falsification of scientific data. The company agreed to pay 100 million German marks to support children affected by Thalidomide, provided they be released from further claims by health and pension insurers [8]. While Chemie-Grünenthal has never admitted liability, they finally issued a formal apology to the public in 2012. The company continues to contribute to the German Federal Contergan Foundation, which provides financial assistance to Thalidomide victims in the form of monthly pensions and one-time payments. However, little compensation has been paid to victims outside Germany, largely due to legal difficulties in organizing international lawsuits.

In Canada, the Food and Drugs Act was amended in 1963 to strengthen drug safety measures. These amendments introduced mandatory reporting of adverse drug reactions and established more rigorous pre-market testing requirements [9]. The UK responded similarly, passing the 1968 Medicines Act. This legislation stipulated that medications could not be approved solely on the basis of animal testing and introduced a Yellow Card Scheme, which allowed any UK citizen to report adverse drug reactions [10]. Across Europe, the formation of the European Medicines Agency (EMA) represented a significant step toward standardizing pharmaceutical regulation. Scientific experts from the European Union collaborated to pool resources and expertise and the agency published comprehensive medical information in accessible language to keep the general public informed about recent drug approvals and recalls [11]. 

The disaster also fundamentally changed the legal concepts of duty of care and negligence in pharmaceutical law. Duty of care refers to the obligation of manufacturers to “act reasonably and avoid causing harm to patients” [12]. This includes thorough testing of products, detailed warnings about potential side effects, proper dosage recommendations, etc. Failure to do these things, or intentionally choosing not to, is negligence. As a result, courts began recognizing and applying these concepts more frequently, especially in pharmaceutical cases involving vulnerable populations like pregnant women. The principle of strict liability became a central standard: manufacturers could be held responsible for injuries caused by their products, regardless of how diligent their testing and production processes may have been [13]. 

But while strict liability ensures patient safety, it has significant downsides that limit its application in the United States. Removing the need for plaintiffs to prove negligence would undoubtedly create a culture of fear within the pharmaceutical industry, where manufacturers constantly worry about the potential for lawsuits, even for rare or unforeseen side effects. The fear of being held liable would result in overly cautious decision-making, leading to delays in bringing beneficial drugs to market and billions more dollars spent on redundant testing every year [13]. Recognizing that all adverse effects of a drug cannot be anticipated in pre-approval studies and hoping to mitigate this culture of fear, the FDA maintains a system of post-marketing surveillance and risk assessment programs. This includes periodic, unannounced inspections of drug manufacturing facilities and mandates manufacturers report any accidents, errors, or quality issues related to their drug [14]. In this way, the FDA promotes scientific advancement while prioritizing consumer safety.

These methods proved effective in the case of Wyeth v. Levine (2009). Petitioner Wyath manufactured an anti nausea drug called Phenergan, which Ms. Levine received via intravenous injection to prevent allergies and motion sickness. She soon developed gangrene, a serious condition in which tissue dies due to lack of blood supply, and underwent emergency amputation of the forearm. Ms. Levine brought a state-law damages action, alleging that Wyeth had failed to provide adequate warning about Phenergan’s side effects [15]. In a 6-3 decision, the court ruled in favor of Levine, determining that Wyeth bore ultimate responsibility for the content of its drug labels. While some side effects may be unforeseen, the Court found that Wyeth had not provided a sufficiently detailed warning about the risks of Phenergan when administered via IV injection. Ms. Levine provided proof of negligence to charge Wyeth with damages. If this legal process had been based solely on strict liability, Wyeth would have been held liable for damages simply because a patient was harmed by their drug. Instead, a thorough investigation made the decision more equitable, establishing Wyeth’s negligence before imposing penalties.

Regulatory framework for pharmaceuticals has improved drastically since the Thalidomide disaster, but several areas still require attention. Many argue that current penalties are not severe enough to deter profit-motivated shortcuts in safety protocols. Increasing these penalties would make it harder for unethical companies to cut corners, without hindering the work of legitimate manufacturers. Others think the implementation of mandatory long-term monitoring programs, extending 10-20 years post-market introduction, would help identify and address delayed drug effects not apparent in initial testing phases. While the FDA has a process like this, it is based on the risk classification of a drug at approval. Drugs deemed high-risk undergo extended clinical studies and thorough periodic reviews, while low-risk drugs face less intensive surveillance [16]. Extending long-term monitoring across the board could provide a more uniform approach, ensuring that all medications, regardless of perceived risk, are regulated with equal care.

The pharmaceutical industry continues to evolve post-Thalidomide, with new technologies like gene therapy and personalized medicine presenting novel regulatory challenges. Our challenge now is to honor those affected by Thalidomide by building a regulatory framework as innovative as the medicines it oversees– one that can protect future generations from harm while embracing the remarkable potential of modern medicine to heal and transform lives.

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[1] Neil Vargesson, Thalidomide‐induced Teratogenesis: History and Mechanisms, 105 Birth Defects Res C Embryo Today 140 (2015), https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4737249/ (last visited Feb 21, 2025).

[2] James E. Ridings, The Thalidomide Disaster, Lessons from the Past, in Teratogenicity Testing: Methods and Protocols 575 (Paul C. Barrow ed., 2013), https://doi.org/10.1007/978-1-62703-131-8_36 (last visited Feb 21, 2025).

[3] See [2]

[4] See [1]

[5] Laura M. Glynn & Curt A. Sandman, Prenatal Origins of Neurological Development: A Critical Period for Fetus and Mother, 20 Curr Dir Psychol Sci 384 (2011), https://journals.sagepub.com/doi/10.1177/0963721411422056 (last visited Feb 21, 2025).

 [6] LYNDON M. HILL & FREDRIC KLEINBERG, Effects of Drugs and Chemicals on the Fetus and Newborn (First of Two Parts), 59 Mayo Clinic Proceedings 10 (1984), https://www.mayoclinicproceedings.org/action/showPdf?pii=S0025-6196%2812%2962060-6 (last visited Feb 21, 2025).

[7] See [1]

[5] Frances O. Kelsey, Thalidomide Update: Regulatory Aspects, 38 Teratology 221 (1988), https://onlinelibrary.wiley.com/doi/10.1002/tera.1420380305 (last visited Feb 21, 2025).

[6] Jeremy A. Greene & Scott H. Podolsky, Reform, Regulation, and Pharmaceuticals — The Kefauver–Harris Amendments at 50, 367 N Engl J Med 1481 (2012), https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4101807/ (last visited Feb 21, 2025).

[7] DDreg Pharma, What Is the Bundesinstitut Für Arzneimittel Und Medizinprodukte (BfArM)?, ddregpharma, https://www.ddregpharma.com/what-is-bfarm (last visited Feb 21, 2025).

[8] The Thalidomide tragedy in Germany, /the-thalidomide-tragedy, https://www.thalidomide-tragedy.com/the-history-of-the-thalidomide-tragedy (last visited Feb 21, 2025).

[9] Health Canada, Thalidomide Survivors Contribution Program, Government of Canada (2019),https://www.canada.ca/en/health-canada/services/thalidomide-survivors-contribution-program.html (last visited Feb 21, 2025).

[10] How medical research changed after thalidomide, (2020), https://www.medicalnewstoday.com/articles/how-the-thalidomide-scandal-led-to-safer-drugs (last visited Feb 21, 2025).

[11] How we work | European Medicines Agency (EMA), (2013), https://www.ema.europa.eu/en/about-us/how-we-work (last visited Feb 21, 2025).

[12] Peter Dwyer, The Duty of the Pharmacist and the Pharmaceutical Industry, 22 Med Law 495 (2003).

[13] strict liability, LII / Legal Information Institute, https://www.law.cornell.edu/wex/strict_liability (last visited Feb 21, 2025).

[14] Center for Drug Evaluation and Research, Postmarketing Surveillance Programs, FDA (2020), https://www.fda.gov/drugs/surveillance/postmarketing-surveillance-programs (last visited Feb 21, 2025).

[15] Wyeth v. Levine (Syllabus) U.S. (2009), https://www.law.cornell.edu/supct/html/06-1249.ZS.html (last visited Feb 21, 2025).

[16] Lembit Rägo & Santoso Budiono, Drug Regulation: History, Present and Future1, Chapter 6 , https://svcp.gnomio.com/pluginfile.php/724/mod_resource/content/1/Drug%20Regulation.pdf (last visited Feb 21, 2025).