The History of Clinical Trials

Humans are naturally inquisitive creatures. We see something happen and we start wondering “Why,” “How,” and “What if.” We are fascinated by the cause and effect relationships that govern events and often go about trying to figure out how to predict or change outcomes. 

The human quest for fact-based, proven knowledge is nothing new. One area that has always been of great interest to scientists is the effect of medicines and other forms of treatment on human health and quality of life. In fact, although documented evidence of this goes all the way back to biblical times, it is easy to imagine that such clinical investigations (involving the use of actual patients) were going on long before recorded history. 

In this article, we will explore the beginnings of clinical trials, tracing a timeline up to the present. To help you better understand the progression of events, however, let’s kick things off by highlighting the distinction between clinical research and clinical trial – two often confused terms.

What Is Clinical Research?

Scientists go beyond just wondering and set about getting answers to their questions by conducting scientific research. They take steps to carefully gather information, as well as to design experiments, record results, and analyze the data generated.1 In the case of clinical research, the experiments are focused on all manner of conditions affecting the human body.

According to the National Cancer Institute, clinical research is:

“Research in which people, or data or samples of tissue from people, are studied to understand health and disease.” 2

What Is a Clinical Trial?

Clinical trials are a subset of clinical research that is concerned specifically with studying interventions. Clinical trials involve the observation of a large group of people in order to assess the effectiveness of selected interventions on their health or health conditions. The interventions may include medications and medical devices, as well as placebos or some other form of control.3

Here are two formal definitions of a clinical trial (again coming from the realm of cancer research, since this is one of the most prolific clinical research areas).

The Moffitt Cancer Center, a nonprofit cancer treatment and research facility, gives the following definition for a clinical trial:

“A clinical trial is a research study that finds new ways to prevent, diagnose or treat disease.”4

Over at the National Comprehensive Cancer Network (NCCN), we find the following definition:

“A clinical trial is a type of research that studies a test or treatment given to people.”5

The NCCN’s definition goes on to point out that both the safety and helpfulness of a test or treatment are what clinical trials focus on.

A Clinical Trials Timeline

There is no way to absolutely say when the very first clinical trial was conducted. Many sources go back to 562 BC, however, and cite the Bible’s Book of Daniel as containing the very first account of a clinical trial (of sorts).

562 BC – King Nebuchadnezzar’s Experiment

It is said that upon conquest of Israel, Babylon’s King Nebuchadnezzar had several Jewish youths, deemed to be both physically fit and intelligent, brought to his palace to be given a Babylonian education. They were to be well taken care of, including being fed plenty of meat and wine. 

Daniel and three friends refused the royal diet and asked the king to allow them to continue having vegetables and water for 10 days to see whether they were any worse off. The king agreed and after 10 days, he finds the Jewish boys to be “ten times better” both physically and mentally than those who had the diet rich in meat and alcohol.6

Of course, this is by no means a true scientific experiment as we would describe one today. It does, however, carry several of the elements of a clinical trial, including being conducted with willing patients or volunteers.

1025 AD – Avicenna’s The Canon of Medicine

Avicenna was a Persian polymath noted for his contributions in a range of fields, including medicine, alchemy, philosophy, psychology, mathematics, and physics. In his medical encyclopedia, The Canon of Medicine, he advises on how clinical trials should be conducted. Among Avicenna’s suggestions is determining how reproducible the effects observed in a clinical trial are.7

He also recommends that drugs being tested be administered to patients with a single condition as opposed to use on a patient with comorbidities as these may complicate analysis of the results. Avicenna also advocated human patients be used in clinical trials instead of animals.

1537 – Ambroise Paré’s Battlefield Ointment

French surgeon Ambroise Paré is credited with conducting the first clinical trial of a novel therapy, though quiet without intending to earn that distinction. Paré toiled on the battlefield trying to save the lives of badly wounded soldiers.8 

He had run out of the boiling elder oil used in the cauterization of wounds and was at a loss of how to treat incoming patients. Using his knowledge of traditional remedies, Paré concocted an ointment of egg yolks, rose oils, and turpentine which he used on the new patients in place of the elder oil and cauterization process.

The next morning, to Paré’s surprise and his great relief, the patients treated with his new intervention were actually doing much better than those who had endured the cauterization process. The “test subjects” displayed none of the swelling, inflammation, fever, and pain that the soldiers treated with the boiling oil and cauterization process were afflicted by.

1747 – James Lind’s Scurvy Trial

This is, perhaps, the most famous of the early examples of clinical trials. It is often cited as the very first true clinical trial to be conducted in modern times. 

Scottish naval surgeon James Lind was concerned about the poor health and high death rate among sailors. He planned, described, and conducted a comprehensive comparative controlled trial of a cure for scurvy which, at the time, ran rampant among sailors.9

He included twelve patients who exhibited similar symptoms of scurvy. They were all fed the same diet and were all kept in the same location. What Lind varied was the treatment given. Separating the sailors into pairs, he gave each pair daily doses of only one of a set of interventions that included: cider; vinegar; two oranges and a lemon; and seawater.

As is now a well-known fact, the citrus remedy worked exceedingly well. It led to citrus, in particular limes, becoming a staple aboard British vessels to the point where British sailors are still referred to as Limeys to this day.

1800 – Austin Flint’s Placebo Trial

Placebos are widely used in modern clinical trials. Placebos and clinical trials did not come together, however, until the 19th Century. A placebo is first defined in Hooper's Medical Dictionary of 1811 as:

“An epithet given to any medicine more to please than benefit the patient.”10

This is noted as the first time the word appears in medical literature. It does not mean, however, that it was not in use well before that or at least in the preceding century.

The first recorded use of placebos in clinical trials took place roughly 50 years later. In 1863, American physician Austin Flint designed an experiment meant to compare the effectiveness of a placebo to that of an active treatment. Flint’s clinical trial is noted as the first one in which the term placebo is used in its current sense as:

“A medical treatment or procedure designed to deceive the participant of a clinical experiment.”11

1944 – The UK Medical Research Council’s Patulin Investigation

It was wartime all around the world when the UK Medical Research Council (MRC) took on a bold project. It conducted the first-ever double blind controlled trial conducted in the general population. It included over 1,000 office and factory workers as part of a clinical trial testing the effectiveness of a penicillin extract called patulin on the common cold.12

The workers volunteered to be a part of the trial and were examined to determine that they did indeed have a cold. Both the patient and the attending medical officer were kept in the dark as to what exactly the treatment was. Treatment was administered every four hours – by a medical team when the patient was at work and by the patient himself or herself when at home.

Disappointingly for the researchers, the results of the experiment did not support use of patulin as a treatment for the common cold. What the trial did, however, is set the stage for the next major milestone in the history of clinical trials – the first randomized controlled trial.

1946 – The UK Medical Research Council’s Streptomycin Trial

Two years after the patulin clinical trial the UK Medical Research Council embarked on what would become one of the major landmarks of modern clinical research and clinical trials. This was the first-ever randomized controlled trial (RCT) and it would go on to overshadow the importance of the patulin investigation in the history of clinical research. It was the MRC’s investigation of streptomycin in the treatment of pulmonary tuberculosis.13

The committee overseeing the streptomycin clinical trial was set up in 1946 and the actual trial began in 1947. This experiment stood out from other clinical trials conducted around the time, not just by being the first RCT but in the way in which the researchers meticulously, methodically, and systematically carried out each aspect of the trial.

Patients were randomly placed in either the streptomycin treatment group or in the group whose treatment was bed-rest. Even analysis of patient x-rays was randomized, as doctors doing the evaluation were unaware of what treatment the patient whose x-ray they were looking at had received. 

Post World War II – The Nuremberg Code and the Kefauver-Harris Amendments

At the end of the Second World War, much of the scientific community was left in shock at the human experimentation atrocities that had been carried out by the Nazis. This prompted the passage of the Nuremberg Code which actually had its beginning in pre-war Germany.14

The Nuremberg Code emphasizes the importance of participants in a study doing so willingly and voluntarily. It also highlights the need for procedures to be conducted in such a way as to ensure the safety of both those conducting the research and those taking part. 

The 1962 Kefauver-Harris amendments went a step further, emphasizing the need for informed consent before volunteers are included in clinical studies. Sadly, however, the Kefauver-Harris amendments were spurred by the thalidomide tragedy in which approximately 10,000 babies were born with birth defects due to their mothers being given this new drug in the early stages of their pregnancy.15

Currently – The Internet’s Role in Assisting Clinical Trials

Nowadays, clinical trials are fully focused on ensuring that participants are properly informed before they are signed onto any trial. Also, patient well-being is of paramount importance at each stage of the trial. These points are often communicated in the public sphere in the hopes of getting more and more persons to volunteer to take part in clinical trials. And, this strategy has worked to a large extent. 

We are now at the point where volunteers can, and often do, find out about and sign up for clinical trials online. Websites, such as Clinical Match, make it easy for patients, physicians, and principal investigators to find each other. Services such as complete clinical trial management and maintaining a database of clinical trials, let these websites streamline the relationship between investigators and participants.

In Summary

Clinical trials play a vital role in how we understand various medical conditions and diseases, as well as in the discovery of treatments that are best suited for them. Our natural curiosity drives the evolution of clinical trials while the application of sound scientific practices ensures the efficacy of the results. 

Looking back, we truly have come a long way. We have gone from the first informal clinical trial conducted by Daniel and King Nebuchadnezzar to Paré’s clinical trial born out of his desperation to save the lives of soldiers and onto the clinical trials of today that are spearheaded by the MRC’s meticulous approach. 

Where shall we go from here? No one knows for sure. What we do know is that clinical trials will always have a place in the scientific landscape as long as we continue to question “Why,” “How,” and “What if.”

References

1. Andersen, Hanne and Hepburn, Brian, "Scientific Method", The Stanford Encyclopedia of Philosophy (Summer 2016 Edition), Edward N. Zalta (ed.), 

URL = <https://plato.stanford.edu/archives/sum2016/entries/scientific-method/>.

2. Clinical Research, NCI Dictionary of Cancer Terms, National Cancer Institute

https://www.cancer.gov/publications/dictionaries/cancer-terms/def/clinical-research

3. NIH's Definition of a Clinical Trial, Grants & Funding, National Institute of Health

https://grants.nih.gov/policy/clinical-trials/definition.htm

4. Clinical Trial Definitions, Moffitt Cancer Center  

https://moffitt.org/clinical-trials-research/clinical-trials/clinical-trial-definitions/

5. What is a Clinical Trial, Patient and Caregiver Resources, National Comprehensive Cancer Network

https://www.nccn.org/patients/resources/clinical_trials/explanation.aspx

6. Weingarten S (2018). Food in Daniel 1:5-16: the first report of a controlled experiment? JLL Bulletin: Commentaries on the history of treatment evaluation (https://www.jameslindlibrary.org/articles/food-daniel-15-16-first-report-controlled-experiment/)

7. Ibn Sina's Canon of Medicine: 11th century rules for assessing the effects of drugs, Mona Nasser, Aida Tibi, Emilie Savage-Smith, J R Soc Med. 2009 Feb 1; 102(2): 78–80. doi: 10.1258/jrsm.2008.08k040

8. Ambroise Paré and the Birth of the Gentle Art of Surgery, Charles B. Drucker, Yale J Biol Med. 2008 Dec; 81(4): 199–202.

9. James Lind (1716-94), Brought to Life, Exploring the History of Science, Science Museum, http://broughttolife.sciencemuseum.org.uk/broughttolife/people/jameslind

10. Arthur K. Shapiro (1964) A Historic and Heuristic Definition of the Placebo, Psychiatry, 27:1, 52-58, DOI: 10.1080/00332747.1964.11023375

11. Is the placebo effect real?, Medical News Today, 

https://www.medicalnewstoday.com/articles/306437

12. The road to randomisation: patulin and the common cold, UKRI Medical Research Council,

 https://mrc.ukri.org/news/blog/the-road-to-randomisation-patulin-and-the-common-cold/

13. The MRC randomized trial of streptomycin and its legacy: a view from the clinical front line

J Crofton, J R Soc Med. 2006 Oct; 99(10): 531–534.

14. The Nuremberg Code, History, National Institutes of Health,
https://history.nih.gov/research/downloads/nuremberg.pdf

 

15. Kefauver-Harris Amendments Revolutionized Drug Development, Consumer Updates, U.S. Food and Drug Administration, https://www.fda.gov/consumers/consumer-updates/kefauver-harris-amendments-revolutionized-drug-development

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