A fascinating history of clinical trials from their beginnings in Babylon
Clinical trials are required to test treatments for COVID-19. Take a quick trip over 2,000 years and discover how our current understanding of clinical trials was formed.
Clinical trials
Clinical trials are currently being undertaken to test treatments and vaccines for COVID-19. There are many different types of clinical trial design, from a simple before and after (measure something in patients, do an intervention like giving them a drug, then measure them again), to a randomized controlled trial, the gold standard of all clinical trial designs.
Here is a light-hearted history of how clinical trials developed over the last two thousand years, including the first recorded instances of control groups, the use of placebos and randomization. It will give you a better understanding of how clinical trials are designed.
600 BC Daniel and his kosher diet
Surprisingly, the first ever clinical trial is found in the Bible in Book one of Daniel and took place in Babylon. In 600 BC, some captive children of the Israeli royal family and nobility were taken into the King Nebuchadnezzar’s service in Babylon — among them were Daniel and three friends. Supposedly, these were golden young men — physically perfect, handsome, intelligent, knowledgeable and well qualified to serve in the king’s palace.
The king ordered Ashpenaz, the chief of his court officials, to teach them the language and literature of the Babylonians, and the king assigned them a daily amount of food and wine from the king’s table. They were to be trained for three years, and after that they were to enter the king’s service. In those days it was believed that consuming good meat and wine produced handsome people!
But Daniel, being a good Jewish boy, did not want to eat non-kosher food and wine, and told Ashpenaz he would not eat it. However, Ashpenaz was worried that if Daniel did not have the royal food and wine, he would lose his good looks.
Daniel suggested a trial. He and his three friends should be provided with beans to eat and water to drink for ten days. If at the end of that time their faces were uglier than those children having the meat and wine, then Daniel would accept the new food.
At the end of the ten days the four boys looked healthier and better nourished than any of the young men who ate the royal food. So, the guard took away the meat and wine and gave them beans and water instead.
Of course, we now know that pulses such beans, peas and lentils have significant nutritional and health advantages and are associated with reduced mortality from coronary heart disease. Whether or not they make you less ugly is another matter!
854–925 Muhammad ibn Zakariya al-Razi and meningitis
Let us now move forward some 1400 years to the 9th Century, when Baghdad was only 50 years old. There were many physicians in Baghdad practicing medicine primarily based on Greek texts. Of all the physicians in Baghdad, one stands out as being exceptional, namely Abu Bakr Muhammad ibn Zakariyya al-Razi (but let’s call him Razi for short).
Razi was a Persian and Islamic polymath — that is, someone knowledgeable about many disciplines. In fact, he was a mathematician, physician, alchemist, and philosopher. He also wrote on logic, grammar, and astrology. He was the first to discover the disinfectant properties of alcohol and thus was the inventor of alcohol-based hand sanitiser. In other words, the sort of guy we could do with during the COVID-19 pandemic!
He wrote many medical textbooks, the largest and most important being “The comprehensive book of medicine”, a collection of medical notes that Razi made throughout his life. It contained extracts from everything he had read, as well as observations from his own medical experience. In his textbook, he discusses what we now know as the early symptoms of meningitis.
The textbook reads: ‘If the dullness in the head is greater than the pain, and there is no insomnia, but rather sleep, then the fever will abate, but the throbbing will be immense but not frequent and he will progress into a stupor.
So when you see these symptoms, then proceed with bloodletting. For I once saved one group of patients by it, while I intentionally neglected to bleed another group. By doing that, I wished to reach a conclusion. And so all of these latter contracted meningitis.’
What Razi is describing, is the use of a control group, one of the cornerstones of modern clinical trials.
1061 Ben Cao Tu Jing and the man root
We now skip another couple of hundred years to China, where in 1061 the Ben Cao Tu Jing or Atlas of Materia Medica was published. The Atlas was compiled and edited by Song Su, a renowned administrator, diplomat, and military strategist. Song Su was also an expert in medicine, astronomy, mathematics, mechanics, and engineering.
In the Atlas we find the following paragraph:
“It was said that in order to evaluate the effect of genuine Shangdang ginseng, two persons were asked to run together. One was given the ginseng while the other ran without. After running for approximately three to five li [about 1500 to 2500 meters], the one without the ginseng developed severe shortness of breath, while the one who took the ginseng breathed evenly and smoothly.”
It sounds a bit like an advert for batteries — however, clearly this was actually a well-described controlled trial! The English word ginseng derives from the Chinese term for “man root” (referring to the root’s characteristic forked shape, resembling the legs of a man). The botanical name for ginseng, Panax, means “all-heal” in Greek, sharing the same origin as panacea.
Today, ginseng is one of the most popular herbal remedies, and a number of health claims are made for it. Interestingly, a recent scientific review found some evidence that ginseng might be helpful for men having trouble with erectile dysfunction.
1537 Ambroise Paré and boiling oil
In France in the 16th Century, Ambroise Paré was a leading surgeon. In fact, he was the royal surgeon to kings Henry II, Francis II, Charles IX, and Henry III. He is considered to be one of the fathers of surgery, and a leader in surgical techniques and battlefield medicine. He was also the inventor of several surgical instruments.
Unfortunately, in those days, battlefield wounds were treated by cauterising them with boiling oil.
In 1537 while treating battlefield wounds, Paré ran out of boiling oil. So instead, he used an old treatment that he had heard of. The remaining patients were treated with an ointment made from egg yolk, oil of roses and turpentine and left overnight. When he returned the following morning, he discovered that the soldiers treated with the boiling oil were in agony, while the ones treated with the ointment had recovered.
We now know that this is because of the antiseptic properties of turpentine. Despite his findings, boiling oil was still used as the preferred treatment for wounds until many years later!
1772 William Cullen and the placebo
Placebo is a Latin word meaning “I shall please”. It was popularized around 1225, since it was the first word uttered in the Vespers in the first Office for the Dead. Interestingly, its opposite is nocebo, which means “I shall harm”.
From this time on, the term took on a disparaging, secular meaning. Mourners were paid to attend a funeral to ‘flatter’ the dead. These paid mourners were said to “sing placebos” of false and easy praise.
In fact, until the 18th Century, it could be argued that all medicine was placebo in that it aimed to please. As the medical historian W.R. Houston wrote, doctors themselves “were the therapeutic agents by which cures were effected.”
The first use of the word placebo in the medical context that we use it now can be ascribed to William Cullen in 1772. William Cullen was Scottish physician, chemist and agriculturalist, and a leading British physician in the 18th century. He employed regular drugs as placebos, although at very low doses. Cullen regarded a ‘placebo’ treatment as one given to please, but without any curative intent or hope.
The idea of placebo as a diluted but active substance persisted into the 19th century. Hooper’s 1812 Medical Dictionary defines a placebo as “an epithet given to any medicine adapted more to please than to benefit the patient”.
But the term also eventually came to mean a physiologically inert substance. Inert substances began to be used in comparative clinical trials during the first half of the 19th century.
1786 Caleb Parry and rhubarb
About the same time that Cullen was contemplating placebos, another British physician, Dr Caleb Parry was contemplating rhubarb.
In the late 18th century, rhubarb was popular as a purgative (a laxative) and Parry wanted to find out whether locally grown rhubarb did just as well as the more expensive imported Turkish variety.
In 1786, he undertook a study where he ‘crossed-over’ the type of rhubarb given to each individual patient at different times. He then compared the symptoms each patient experienced while eating each type of rhubarb. In other words, the first published cross-over study (a crossover clinical trial is where the study participants receive each treatment in a random order). In fact, he found no advantage in using the Turkish rhubarb!
Interestingly, rhubarb roots have been used as a laxative for over 5,000 years. The roots and stems are rich in anthraquinones, which have a laxative effect.
1747 James Lind and scurvy sailors
It was May 1847. The British naval ship Salisbury had been at sea for weeks, and on board, sailors were suffering from an all-too familiar sickness.
Scurvy, a revolting and foul-smelling affliction of sailors, was taking its toll on the crew. As more and more members of the ship’s company became ill with the disease, the naval surgeon on board, James Lind, decided to perform an experiment.
On the 20th of May, Lind selected twelve of the scurvy-afflicted sailors for his experiment.
He wrote: “Their cases were as similar as I could have them. They all in general had putrid gums, spots and lassitude, with weakness of the knees”.
The twelve sailors were moved into a cabin on the ship, and Lind ordered that they all be given the same rations. He divided the group into twos and gave each pair of men a different scurvy treatment from the many which were popular at the time.
The first pair received a quart of cider a day
The next pair got 25 drops of ‘elixir of vitriol’ (weak hydrochloric acid)
The third pair received two spoonfuls’ of vinegar
The fourth pair, a pint of sea-water
The fifth pair, a spicy nutmeg paste and a drink of barley water
The final pair were given two oranges and a lemon each day.
The fruit supply ran out after just six days, but by that time the outcome of the experiment was clear. The condition of the men who received the fruit had improved so much, that one of them was returned to duty while the other was appointed nurse to the remaining ten.
Lind’s experiment showed that of the six different treatments, citrus fruits were the most effective anti-scurvy medicine. However, it still took many years before the British navy figured out that giving citrus juice prevented scurvy. And it was not until 1932 that the link between vitamin C and scurvy was established.
1907 William Fletcher and Beriberi
Beriberi is a disease which was common in South East Asia in the early part of the 20th Century. Its symptoms are weakness, loss of appetite and numbness in the arms and legs. It causes progressive damage to nerves and the heart and it can be fatal.
In 1905 a Beriberi epidemic broke out at the Kuala Lumpur Lunatic Asylum. At that time William Fletcher was the district surgeon in Kuala Lumpur. He realised that the epidemic in the asylum provided an excellent chance to run an experiment (which is just a tad ethically dubious!).
The lunatics were counted and assigned a number. Those with even numbers were sent to west ward, and odd numbers to the east ward. The only difference between the two groups was that the odd-numbered residents were given white polished rice to eat, while the even-numbered residents were given brown unpolished rice.
Of the 120 residents who ate white rice, 18 died of Beriberi — a death rate of 15%. Of the 123 residents on a brown rice diet, there were no deaths.
Today we know beriberi is a thiamine deficiency disease, and that a white rice diet is deficient in thiamine.
1948 Sir Austin Bradford-Hill and the randomised controlled trial
Sir Austin Bradford Hill was an English epidemiologist and statistician, who died in 1991. He is credited with having made medical statistics an essential part of modem epidemiology and conducted the first randomized controlled trial (commonly called an RCT). The trial itself was for the treatment of tuberculosis, and he decided whether a patient should be treated with streptomycin and bed-rest, or by bed rest alone by using a table of random numbers.
The details of the which patient got each treatment were unknown to any of the investigators and were contained in a set of sealed envelopes. After acceptance of a patient, and before admission to the centre, the appropriate numbered envelope was opened at the central office: the card inside told if the patient was to be in the streptomycin group. Patients were not told they were in a trial. The used of sealed envelopes is what we now call allocation concealment, and making sure that neither investigators or patients know which treatment they are on is called blinding. These are now standard features of RCTs.
The RCT is now considered the “gold standard” or most ideal clinical trial that we currently use, due to the use of a control group and randomization. So, you can see that although Bradford Hill conducted the first ever RCT, it was based on hundreds of years of very clever people working out why things like a control group and randomization are so important.
I do hope you enjoyed this article. I have written several other about COVID-19. Here are the links:
COVID-19 — facts and fiction
Infectious diseases and their impact on civilisation
Epidemiology and infectious diseases
Are the statistics we see in articles about the Coronavirus accurate?
A fascinating history of clinical trials from their beginnings in Babylon
Should the USA have cancelled funding to the WHO?
