Trial is from the Anglo–French trier, meaning to try. Broadly, it refers to the action or process of putting something to a test or proof. Clinical is from clinic, from the French cliniqué and from the Greek klinike, and refers to the practice of caring for the sick at the bedside. Hence, narrowly, a clinical trial is the action or process of putting something to a test or proof at the bedside of the sick. However, broadly it refers to any testing done on human beings for the sake of determining the value of a treatment for the sick or for preventing disease or sickness. Clinical trials explore how a treatment reacts in the human body and are designed to ensure a drug is tolerated and effective before it is licensed by regulatory authorities and made available for use by doctors. Studies vary in their primary goal or endpoint (i.e. the most important outcome of the trial), the number of patients involved, and the specifics of the study design. However, all clinical studies conform to a strict set of criteria to protect the patients involved and to ensure rigorous evaluation of the drug.
The present work gives a chronological review of the advancements in the methods, ethics and set of rules which must be adopted while a clinical trial is being performed.
Keywords: Clinical trials, Clinical research, James Lind experiment, Phases, Randomization, Placebo, Drug development, US FDA.
The word clinical (from clinic) is derived from the French word cliniqué and Greek work klinike, meaning ‘the practice of caring for the sick on the bedside’. Trial is from the Anglo-french word trier meaning ‘to try’.  Clinical trials refer to the process or action of putting something to test or proof on the bedside. However, clinical trials are defined as the set of experiments and observation performed on animals and/or humans and recorded to explore how a treatment reacts in human body. They are designed to ensure a drug is tolerated and effective before it is approved by regulatory authorities for developing it into marketable product.
Clinical trials involves the application of the experimental variable – treatment to a person or group of persons – and observation during or following application of the treatment to measure its effect. That measure (outcome measure) may be death, occurrence or recurrence of some morbid condition, or a difference indicative of change.
Clinical trials are categorized into different phases, viz. Phase I, II, III, IV. 
- Trial Phase 1: The first investigation of a potential new drug in people, to determine how the drug reacts in the body, and how the body reacts to the drug – how it is absorbed, distributed and metabolized or altered / used by the body. Commonly conducted in a small number of healthy volunteers
- Trial Phase II: The first study to focus on the clinical effectiveness of the drug, and therefore performed in patients with the disease. At this stage the studies also determine any short-term side effects and safety risks associated with the investigational drug.
- Trial Phase III: Studies carried out in large numbers of patients, comparing the investigational drug with the best existing treatment or standard of care in that particular disease. If positive results are obtained all data to date is compiled into a dossier and an application is made to regulatory authorities to request a license for clinical use.
- Trial Phase IV: Also known as Post marketing studies, these are conducted after the drug I approved by the regulatory authorities and may include thousands of patients. These trials are generally designed to evaluate the long-term safety and efficacy of a drug, and to test it in a “real world” setting of daily clinical practice.
All the clinical studies stick to a strict of rules and ethically conduct the trials to ensure patient safety and promote rigorous drug evaluation.
605 BC 
The record of the first ever clinical trial dates back to 605 BC. The Book of Daniel gives an account of a ‘comparative’ diet plan which was designed to test the effects and benefits of vegetarian diet over non-vegetarian one.
In the Chapter 1: Verse 12-15, Daniel said to King Nebuchadnezzar II, “Prove thy servants, I beseech thee, ten days; and let them give us pulse to eat, and water to drink. Then let our countenances be looked upon before thee, and the countenance of the children that eat of the portion of the King’s meat: and as thou seest, deal with thy servants.”
This, when translated to modern day English means, “Please test your servants for ten days, and let us be given some vegetables to eat and water to drink. Then let our appearance be observed in your presence and the appearance of the youths who are eating the king’s choice food; and deal with your servants according to what you see.”
Accordingly, the King ordered a group of children to be kept on a strict diet of meat and wine, while Daniel was given a diet of pulses (beans, pods and lentils) and water. However three children refused to have the King’s diet and opted to eat the vegetarian diet. At the end of 10 days, the King saw that the facial expressions of those who ate pulses were fairer and had flat flesh when compared to their counterparts who ate meat and drank wine. King immediately stopped the trial and the children on non-vegetarian diet were switched to vegetarian diet.
460 BC to 370 BC
Hippocrates of Hos, referred to as Hippocrates, was a Greek Physician of the Classical Greece and is known as ‘Father of Medicine’.  He is believed to have created the oath that bears his name, ‘The Hippocratic Oath’.  This oath is a seminal document on the ethics of medical practice. Even today, the physicians and other healthcare professionals swear by it to practice medicine justly and ethically.
A clause of the oath mentions ‘To do no harm to their patients’, which carries over to the clinical research where the safety of human subjects is of paramount importance. The oath quoted by Hippocrates is still the base of clinical research and had laid a foundation to follow ethical clinical trials, ever since the trials were conducted. [6, 7]
10th Century AD [8, 9]
Ibn Sina or Avicenna was a Persian polymath of the Islamic Golden Age. He has to his credit 40 books on medicine, of which the ‘Al-Quanun fi al-Tibb’ or ‘The Canon of Medicine’ became a standard medical text and was used as late as in 1650. The Canon of Medicine, an Arabic Medicine Encyclopedia, comprised the works of Hippocrates, Galen, Dioscorides and others. It was completed and originally published in 1025 AD.
In this text, Avicenna suggested that, “…the new drugs and medicines be tested on animals, followed by humans before put into general use…” He gave a set of 7 fundamental rules for clinical trials. They are as below: [10, 11]
1) The drug must be pure.
2) The drug must be used on a “simple” disease.
3) The drug must be tested on at least 2 different types of disease.
4) The quality of the drug must correspond with the strength of the disease.
5) The timing of observations should be measured to rule out the effects of natural healing.
6) The drug must show consistency over several trials.
7) A drug should be tested in animals first, thereafter in humans, as the effects in animals and humans may not be the same.
These set of rules needed no modification until the modern day trials were performed on not only simple diseases, but as complex as Cancers. However the essence of these rules still prevails in the practice of clinical trials. Such basic set of rules was another milestone which guided the path towards advanced clinical developments.
15th Century AD [12, 13]
Serendipitous events often lead to discoveries which have lasting effects. Such was a case when Ambroise Paré trialed a new remedy and it replaced the ‘standards’ till then.
Ambroise Paré was a French surgeon who served in for kings Henry II, Francis II, Charles IX and Henry III. He is considered one of the fathers of surgery and modern forensic pathology. More importantly, he was a pioneer in surgical techniques and battlefield medicine, especially in the treatment of wounds. In the year 1537, Paré served as a surgeon at the battle for castle of Villaine. Till that time, the gunshot wounds were treated by pouring boiling oil over the wound. However, Paré ran out of the conventional treatment and he decided opt for an ointment made of Turpentine oil, egg yolks and oil of roses. To his surprise, the ointment was more effective that the ‘standard’ boiling oil treatment and even had fewer side effects than the later one. 
The result of his ‘trial’, as observed by Paré on the morning following the battle is as summarized below: 
“I raised myself very early to visit them, when beyond my hope I found those to whom I had applied the digestive medicament, feeling but little pain, their wounds neither swollen nor inflamed, and having slept through the night. The others to whom I had applied the boiling oil were feverish with much pain and swelling about their wounds. Then I determined never again to burn thus so cruelly the poor wounded by arquebuses.”
This event, by fortune, produced a condition which resembles the modern day feature of drug discovery and clinical trials. This event made it clear that even the so called ‘standard drugs of therapy’ can be replaced by newer drugs provided that the later chemical entity is of equal or higher potency than the standard and has less adverse effects than the general use drugs.
17th Century AD
All the trials conducted until these times were uncontrolled, i.e. they were not simultaneouslycompared with a standard reference. The essential features of the modern day clinical trials have much reminiscence from the James Lind’s summary of clinical trial.
James Lind was a Scottish physician and a pioneer of naval hygiene in the Royal Navy, the United Kingdom’s Naval Warfare Force. He was the first ever to introduce a Control in the clinical trials and hence regarded as the originator of the modern clinical trials.
In 1753, when Dr. Lind was a resident in Edinburgh and a Fellow of the Royal College of Physicians, he published the Treatise which contains description of his controlled-trial with oranges and lemons and a systematic review of previous literature on scurvy titled ‘Explaining and illustrating the evolution of fair tests of medical treatments’.
Lind’s “Treatise on Scurvy” has an account of his clinical trial performed in 1747, which is as given below: 
“On the 20th of May 1747, I took twelve patients in the scurvy, on board the Salisbury at sea. Their cases were as similar as I could have them. They all in general had putrid gums, the spots and lassitude, with weakness of their knees. They lay together in one place, being a proper apartment for the sick in the fore-hold; and had one diet common to all, viz., water gruel sweetened with sugar in the morning; fresh mutton-broth often times for dinner; at other times puddings, boiled biscuit with sugar, etc; and for supper, barley and raisins, rice and current, sago and wine, or the like.
Two of these were ordered each a quart of cider a day.
Two others took twenty five guts of elixir vitriol three times a day, upon an empty stomach; using a gargle strongly acidulated with it for their mouths.
Two others took two spoonfuls of vinegar three times a day, upon an empty stomach; having their gruels and their other food well acidulated with it, as also the gargle for their mouth.
Two of the worst patients, with the tendons in the ham rigid, (a symptom none of the rest had), were put under a course of seawater. Of this they drank half a pint every day and sometimes more or less as it operated, by way of gentle physic.
Two others had each two oranges and one lemon given them every day. These they eat with greediness, at different times, upon an empty stomach. They continued but six days under this course, having consumed the quantity that could be spared.
The two remaining patients, took the bigness of a nutmeg three times a-day, of an electuary recommended by an hospital surgeon, made of garlic, mustard-seed, rad. raphan, balsam of Peru, and gum myrrh;
…using for common drink, barley-water well acidulated with tamarinds; by a decoction of which, with the addition of cremor tartar, they were gently purged three or four times during the course…
The most sudden and visible good effects were perceived from the use of oranges and lemons, one of those who had taken them being at the end of six days fit for duty.”
The results of this trial were clear but Lind hesitated to recommend the use of oranges and lemons because they were too expensive. About 50 years later, the British Navy eventually made lemon juice a compulsory part of the seafarer’s diet and this was soon replaced by lime juice because it was cheaper.
This trial conducted by James Lind followed, not only all the previous theories and set of rules proposed for conduct of an ethical and just trial, but also introduced the most important feature of modern clinical development, The Control.
18th Century AD
Concept of Placebo 
It was only until 1863, when Austin Flint introduced Placebo-controlled trials, that the newly discovered drug molecules were compared with the standard reference or the general use drug.
Austin Flint was an American physician and was a founder of Buffalo Medical College, precursor to The State University of New York at Buffalo. Flint was the first to coin the termplacebo or placeboic remedy and was used to refer to a dummy simulator in a clinical trial.
In 1863, Flint administered a Placebo treatment to 13 inmates who were suffering from rheumatic fever at the Long Island College Hospital.
Flint quoted in his ‘A Treatise on the Principles and Practice of Medicine’,
“…to secure the moral effect of a remedy given specially for the disease, the patients were placed on the use of a placebo which consisted, in nearly all of the cases, of the tincture of quassia, very largely diluted. This was given regularly, and became well known in my wards as the placeboic remedy for rheumatism…”
To his surprise, 12 of the 13 patients showed no significant difference between the results of the active treatment and his placebo in terms of disease duration, duration of convalescence, number of joints affected and emergence of complications. In the 13th case, Flint raised a possibility that the other complications that had emerged (pericarditis, endocarditis, and pneumonia) would have been prevented if the patient was given the ‘active’ treatment.
This trial conducted by Flint involved no comparison of the active drug and placebo in a same trial. But still it was a deviation from the then practice of comparing the effects of active remedy to what Flint described as the ‘Natural history of untreated disease’.
Concept of randomization
Charles Sanders Peirce & Joseph Jastrow in 1885 demonstrated that the intensity of the sensation increases continuously with the excitation. They performed a series of experiments to test the ability of humans to perceive and differentiate between differences in weight and pressure. To bias their experiments, the volunteers were blindfolded and were subjected to choosing a card from a specialized deck. The weights on the scale were added as per the volunteers’ perception. [18, 19]
This psycho-evaluative experiment was no where related to clinical trials but was considered to be the first ever experiment involving a bias-free and randomized procedure.
In, 1923, R. A. Fischer performed an experiment on crop variation and is believed to be the first to employ the concept of randomization in his agricultural experiment. [20, 21]
In 1926, J. Burns Amberson performed a trial on patients at the Detroit Municipal Tuberculosis Sanatorium, to test a drug for tuberculosis. In this trials the 24 patients were divided into 2 groups based on the clinical, X-ray and laboratory tests. The type of treatment, i.e. the control and the active, was decided through a flip of coin. 
The first trial which is attributed to have utilized “proper” randomization was the British Medical Research Council’s trial in 1948, performed to evaluate the effects of streptomycin in tuberculosis. The patients for this study were assigned to different groups (streptomycin and bed rest or best rest alone) using random sampling numbers and sealed envelopes. Additionally, blinded assessment was employed, and neither the researchers nor the patients knew in which treatment group the patients were in at the time of the study. 
The sole purpose of randomizing a clinical trial is to avoid selection bias in the formation of treatment groups. The goal of randomizing a clinical trial is to create groups that provide a valid basis for comparison. The hallmarks of a sound randomization are reproducible order of assignment; documentation of methods for generation and administration of assignments; release of assignments only after essential conditions satisfied; masking of assignments to all concerned until needed; inability to predict future assignments from past assignments; clear audit trail for assignments; and the ability to detect departures from established procedures.
A rigorous, randomized and well-controlled trial is referred to as Gold standard in clinical research.
19th Century AD
Prior to the World War-II, German physicians and the Nazi extremists were proponents of the use of racial hygiene in order to accomplish racial purity in Germany and exterminate the Jews. Over 3.5 million sterilization operations, illegal experiments on citizens and unethical practices were prevalent in pre-war period. In response to these, Alfons Stauder, member of the Reich Health Office, criticized the physicians saying that the “dubious experiments have no therapeutic purpose”. 
After World War-II, a series of trials (known as Doctors’ Trials) were held at Nuremberg Germany, to hold members of the Nazi party responsible for the war crimes. On August 20, 1947, the judges delivered their verdict against Karl Brandt and 22 others. Meanwhile, in May 1947, six points defining legitimate medical research were submitted to the Counsel for War crimes. The Judges adopted the six points and added 4 more points to it and prepared, what came to be known as, The Nuremberg Code.
The 10 point codes of ethical conduct of human experimentation are as follows: [25, 26]
- Required is the voluntary, well-informed, understanding consent of the human subject in a full legal capacity.
- The experiment should aim at positive results for society that cannot be procured in some other way.
- It should be based on previous knowledge (e.g., an expectation derived from animal experiments) that justifies the experiment.
- The experiment should be set up in a way that avoids unnecessary physical and mental suffering and injuries.
- It should not be conducted when there is any reason to believe that it implies a risk of death or disabling injury.
- The risks of the experiment should be in proportion to (that is, not exceed) the expected humanitarian benefits.
- Preparations and facilities must be provided that adequately protect the subjects against the experiment’s risks.
- The staff that conduct or take part in the experiment must be fully trained and scientifically qualified.
- The human subjects must be free to immediately quit the experiment at any point when they feel physically or mentally unable to go on.
- Likewise, the medical staff must stop the experiment at any point when they observe that continuation would be dangerous.
Unethical clinical practices and unacceptable human experimentation in Germany were contrasting to the Hippocratic Oath and hence needed to be nipped in time.
The Declaration of Helsinki 
With advancements in clinical research, the ethics for performing clinical research needed to be updated. The Declaration of Helsinki was adopted by World Medical Association in June 1964 in Helsinki, Finland. The Declaration expands on the Nuremberg Code by applying the doctrines specifically to clinical research. Since it was adopted, the declaration has undergone seven revisions, with the most recent at the General Assembly in October 2013. The Declaration is the first significant effort of the medical community to regulate research itself and hence is regarded as an important document concerned with the human experimentation.
Apart from the global efforts to establish ethical clinical trial procedures, individual countries have developed their own systems for regulating the conduct of clinical trials. The 3 most influential institutions include the Food and Drug Administration (FDA) of the United States, the European Medicines Agency (EMEA), and Japan’s Pharmaceuticals and Medical Devices Agency (PMDA).
Clinical trials and human experimentation are an irreplaceable part of the drug development process. Trials have been performed since ages, may it be the Daniels trial of vegetarian diet, or Paré’s trial of a replacement of the standard, or Lind’s trials of scurvy and oranges. There have been significant advancements in the ways of testing drugs. The controls were introduced to have a standard reference, trials were randomized to avoid the possibility of getting biased results, the placebos were brought in to study effect of psychology on disease therapy, and ethical codes were modified and adopted to favor voluntary participation of subjects.
Although the clinical trials developed all through the centuries, it is only the 21st century that the Clinical development field has witnessed an ethical and focused growth. Over the times, what has remained same is the need to be ethical in trials. Each of previous researchers’ trials was modified in its flaws and higher ethical standards were introduced. Similar human essence is expected in the future endeavors.
Statistics and technology involved in trials and research have been thoroughly utilized to select the most beneficial drug candidate. From over 10000 drug molecules discovered, only one molecule makes its way to become a marketable product. Stringency in the clinical research can be seen through these numbers.
Conclusively, clinical studies can be viewed as that part of drug development process which has to role of sifting the drug molecules which, if used for general therapy, may prove to be fatal. The rigorous process of clinical trials goes with saying, ‘A stitch in time saves nine’.
- Mahan V.L., Clinical Trial Phases, International Journal of Clinical Medicine, Vol. 5, 2014, 1374-1383.
- American Bible Society (1816). The Holy Bible: Old and New Testaments, King James Version (1611). American Bible Society, New York.
- Hulkower R. The History of the Hippocratic Oath: Outdated, Inauthentic, and Yet Still Relevant. EJBM. 2009/2010;25/26(1): 41-4.
- Mahdi M, Gutas D, Abed SB, et al. Avicenna. Encyclopedia Iranica. London: Routledge and Kegan Paul; 1987. Volume 3.
- Savage-Smith E. Medicine. In: Rashed R, editor. Encyclopedia of the History of Arabic Science, Volume 3. London: Routledge; 1996
- Osler W.The principles and practice of medicine, designed for the use of practitioners and students of medicine. New York, NY: Appleton; 1892.
- Packard, F.R. (1921).Life and Times of Ambroise Paré, 1510–1590. Paul B. Hoeber, New York.
- Donaldson IML, Ambroise Paré’s accounts of new methods for treating gunshot wounds and burns, JLL Bulletin: Commentaries on the history of treatment evaluation,(2004).
- Lind, J. (1753).A Treatise of the Scurvy. Sands, Murray, Cochran, Edinburgh. Reprinted in Lind’s Treatise on Scurvy, C.P. Stewart & D. Guthrie, eds. Edinburgh University Press, Edinburgh, 1953.
- Charles Sanders Peirce & Joseph Jastrow(1885). Memoirs of the National Academy of Sciences, 3, 73-83, Presented 17 October 1884.
- Biographical Memoirs of Fellows of the Royal Society of London, 9: 91-120, (1963).
- The J. Burns Amberson Lecture1,2, American Review of Respiratory Disease, 90(4), pp. 505–515.
- Crofton J. The MRC randomized trial of streptomycin and its legacy: a view from the clinical front line.Journal of the Royal Society of Medicine. 2006; 99(10):531-534.
- Trials of War Criminals before the Nuremberg Military Tribunals under Control Council Law No. 10″, Vol. 2, pp. 181-182. Washington, D.C.: U.S. Government Printing Office, 1949.
- Annas GJ, Grodin MA, eds. The Nazi doctors and the Nuremberg Code: human rights in human experimentation. New York: Oxford University Press, 1992.
- World Medical Association Declaration of Helsinki Ethical Principles for Medical Research Involving Human Subjects Adopted by the 18th WMA General Assembly, Helsinki, Finland, June 1964.Sagar Suresh Gilda is a student of Batch I of Biocon KGI Program in Clinical Development. Prior to joining Biocon Academy he did his B.Pharm in Pharmaceutical Sciences from Shivaji University