Famous Clinical Trials

A history of clinical trials

Clinical trials, in a broad sense, i.e., the comparative testing of health or behavioral interventions, have a long history, dating back to before 562 BC, when King Nebuchadnezzar of Babylon recorded a rudimentary assessment of a dietary intervention.[1] He had instructed his men to follow a diet consisting solely of meat and wine, which he considered would optimize their health. However, some men refused and wished instead to eat legumes, which the king permitted out of curiosity. After 10 days, those who followed a strict diet of legumes and water appeared to be better nourished than those on the meat and wine diet, so the king allowed the legume-eaters to continue their practice.[1] While this was far from being a randomized controlled trial – considered the “gold standard” of clinical research today – it is speculated that this could have been the first recorded instance of a medical research event guiding public health decisions.[1]

After that, there are a few recorded instances of stand-out events and advances in medical thinking that resembled or contributed to form the basis of modern clinical research, such as an accidental trial on the use of a novel cauterizing mixture for wounds when supplies of the standard-of-care ran out.[2] Much later, James Lind’s famous scurvy trial in 1747 demonstrated the benefit of citrus fruits in preventing scurvy, and that study is commonly cited as the first controlled trial.[2]

Aspects of the modern structure of clinical research – and especially the regulations governing clinical trials – were not put into place until much more recently. In 1863, an American physician Austin Flint conducted the first known use of a placebo in comparison against an established remedy.[2] The first double-blind controlled trial was then carried out by the UK’s Medical Research Council (MRC) in 1943 to 1944, investigating the effectiveness of patulin – an extract of a type of penicillin – against the common cold, which, despite being a landmark study, showed no protective effect of the treatment.[2] While being a controlled and double blinded study, it still did not involve a strict randomization procedure, but rather an alternation procedure (strictly rotating from one assignment to the other between patients). 1947 saw the first randomized controlled trial, also conducted by the UK MRC, to investigate streptomycin for pulmonary tuberculosis. Sir Bradford Hill, of the study’s statisticians, had developed the ideas of randomization over a few years, with the added feature of allocation concealment (essentially blinding). This study officially marked the introduction of the statistical process of randomization into clinical research, and also features other robust statistical features such as objective outcome assessment measures. Still to this day, the streptomycin study is considered a landmark trial in advancing the quality of clinical research.

Landmark trials in different therapeutic areas

There are other landmark trials which have shaped specific therapeutic areas. For example, in cardiology, the Framingham Heart Study, which began in 1948 and is still ongoing today, brought groundbreaking insights into the underlying causes of cardiovascular disease and suggested some prevention methods. It was this study that either established the first evidence – or solidified prior evidence/suspicions – of links between cholesterol and lipoprotein (LDL and HDL) levels, physical exercise, dietary factors, diabetes, obesity, and smoking with cardiovascular disease.[3]

In the field of psychiatry, The STAR*D (Sequenced Treatment Alternatives to Relieve Depression) study, which was completed in 2006, is considered a landmark study in how depression treatment is approached. The STAR*D study enrolled over 4 thousand patients and was designed to be more generalizable than other studies by using more relaxed (i.e., minimal) eligibility criteria and not using blinding. It involved a comparative analysis of different treatment modalities for depression cases wherein first-line antidepressants did not work. Although it has since been extensively criticized for questionable scientific validity and exaggeration of its outcome measures (primarily, patients achieving complete remission of their depression), it provided the basis for the approach of making treatment decisions on the basis of individual response to prior treatment attempts and outcomes.[4]

For an overview of some other landmark clinical trials, ranked by the number of citations they’ve received in academic journal articles, check out 2 Minute Medicine’s “Classics in Medicine: Summaries of the Landmark Trials” publication.[5] According to this compilation, the “UK Prospective Diabetes Study” (UKPDS) has been cited 20,000 times. UKPDS was a landmark study that lasted 20 years (1977 to 1997), which demonstrated that common complications of diabetes could be prevented through adequate control of blood pressure and/or blood glucose levels.[6]

Famous clinical trials for vaccines

Famous clinical trials related to the development of vaccines that are still in use today, include:

The Polio vaccine trials in 1954, which were controversial at the time but which eventually led to the implementation of a highly effective vaccine against Polio.[7]

An extensive series of trials that culminated in the combination of vaccines for measles, mumps, and rubella, which is still used today and has essentially eradicated these 3 viral diseases from extensive geographical areas.[8]

More recently, various clinical trials were rolled out to study the effectiveness of vaccines protecting against SARS-CoV-2 (i.e., the Covid-19 virus). A phase III trial that enrolled over 43,000 participants demonstrated 95% protection with Pfizer-BioNTech’s BNT162b2 vaccine.[9] Moderna’s mRNA-1273 vaccine was also shown to have high efficacy (>94%) in a phase III trial that recruited over 30,000 participants in the US.[10]

Famous clinical studies gone wrong

Of course, there are some clinical studies that have become famous for other reasons. Here, we briefly overview three famous failed clinical trials, simply in order to highlight the importance of robust safety testing and ethical procedures in clinical research – both of which are continually improved by learning from such mistakes and unexpected problems. These failed clinical trials have, at the very least, led to stricter regulations industry-wide meant to protect patient safety.

1. TGN1412 (2006)

Sometimes known colloquially as the “Elephant Man” study, a 2006 first-in-human phase I trial sponsored by Parexel of the drug theralizumab, or TGN1412 (developed by TeGenero Immuno Therapeutics) resulted in hospitalization of six subjects for severe and systemic organ failure.[11] Despite administering a supposedly sub-clinical dose (typical of first trials in humans) 1/500th of the “safe dose” established in preclinical animal studies, the drug – a strong agonist of the CD28 receptor of immune T cells – turned out to cause severe cytokine release syndrome. All six of the eight randomized volunteers who received the drug were hospitalized within 16 hours of receiving the first administration of the drug.

2. Thalidomide

Thalidomide is a drug that was developed in 1953 and 1954 in Switzerland and Germany, respectively, with the intention for use as a non-addictive sedative drug, which was also effective as an antiemetic (to prevent nausea vomiting) amongst pregnant women. Originally passing through clinical trials with flying colors - minimal side effects and seemingly no toxicity or maximum dose limit – it was not until 4 years later that thalidomide was directly, causatively linked to birth defects in infants born to mothers who had taken the drug – even just once during pregnancy.[12] Thalidomide went down in history, but for all the wrong reasons, with estimations identifying over 10,000 infants affected by exposure to the drug – almost 40% of whom died within their first year of life – and likely additional cases that went unrecorded.[13] Interestingly, thalidomide was denied approval in the USA by the FDA officer Dr. Frances Kelsey, which prevented a large-scale tragedy in the country and later led to her being awarded the President’s Award for Distinguished Federal Civilian Service, in 1962, by John F. Kennedy.

Perhaps even more interestingly, interest in thalidomide has since been revitalized, particularly for its antiangiogenic properties (potentially useful in treatment of certain cancers) and its utility in treating erythema nodosum leprosum (ENL), discovered by an Israeli physician, Dr. Jacob Sheskin, in 1964.[13] This case illustrates the complexity of clinical research, where things are far from predictable, and wherein new indications for drugs commonly arise from initial failures.

3. BIA 10-2474 Phase I trial (2016)

A 2016 phase I trial conducted in France by Portugal’s Bial Pharmaceuticals on a fatty acid amide hydrolase (FAAH) inhibitor, BIA 10-2474, resulted in irreversible brain damage in four subjects and the death of another, after unexpected severe adverse events. There are numerous potential factors theorized to have played a role in this tragic outcome, including cumulative toxicity, inappropriate animal studies, drug impurities, and dose calculation issues, amongst others; more details can be read in this article.[14] This unfortunate trial has been extensively reviewed and various lessons have been extracted in order to further strengthen the thoroughness of oversight in clinical research and enhance patient safety protections.[14]

Conclusion

While some clinical trials may be well-known for tragic outcomes, these are still relatively rare considering the sheer number of clinical trials carried out worldwide. Other trials have gone down in history for leading to medical advances and policy shifts that have significantly improved public health and saved countless lives. We hope that this article has helped shed light on the complex history of clinical research, and helps you appreciate how far we have come in a relatively short amount of time. With currently emerging technologies and research methods, the potential for further breakthroughs is accelerating every day, and patient safety and well-being is being increasingly prioritized and safeguarded along the way.