Abstract
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.
INTRODUCTION
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’. [1] 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. [2]
Trial phase
|
Definition
|
I
|
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
|
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.
|
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.
|
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.
HISTORY
605 BC [3]
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’. [4]
He is believed to have created the oath that bears his name, ‘The Hippocratic
Oath’. [5] 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. [14]
The result of his ‘trial’, as observed by
Paré on the morning following the battle is as summarized below: [15]
“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 simultaneously
compared 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: [16]
“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 [17]
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 term placebo 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. [22]
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. [23]
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”. [24]
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]
1. Required is the voluntary,
well-informed, understanding consent of the human subject in a full legal
capacity.
2. The experiment should aim at
positive results for society that cannot be procured in some other way.
3. It should be based on previous knowledge
(e.g., an expectation derived from animal experiments) that justifies the
experiment.
4. The experiment should be set up in a
way that avoids unnecessary physical and mental suffering and injuries.
5. It should not be conducted when
there is any reason to believe that it implies a risk of death or disabling
injury.
6. The risks of the experiment should
be in proportion to (that is, not exceed) the expected humanitarian benefits.
7. Preparations and facilities must be
provided that adequately protect the subjects against the experiment’s risks.
8. The staff that conduct or take part
in the experiment must be fully trained and scientifically qualified.
9. The human subjects must be free to
immediately quit the experiment at any point when they feel physically or
mentally unable to go on.
10. 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 [27]
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.
To date
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).
CONCLUSION
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’.
REFERENCES
1. Mahan V.L., Clinical Trial Phases, International Journal of Clinical
Medicine, Vol. 5, 2014, 1374-1383.
2. https://docs.gatesfoundation.org/documents/clinical_trials.pdf
3. American Bible Society (1816). The Holy Bible: Old and New
Testaments, King James Version (1611). American Bible Society, New York.
4. https://www.britannica.com/topic/Hippocratic-oath
5. https://en.wikipedia.org/wiki/Hippocratic_Oath
6. Hulkower R. The History of the Hippocratic Oath: Outdated,
Inauthentic, and Yet Still Relevant. EJBM. 2009/2010;25/26(1): 41-4.
7. https://lsnaith.wikispaces.com/file/view/Hippocratic+Oath.pdf
8. Mahdi M, Gutas D, Abed SB, et al. Avicenna.
Encyclopedia Iranica. London:
Routledge and Kegan Paul; 1987. Volume 3.
9. Savage-Smith E. Medicine. In: Rashed R,
editor. Encyclopedia
of the History of Arabic Science, Volume 3. London: Routledge; 1996
10. Osler W. The principles and practice of medicine, designed for the use
of practitioners and students of medicine. New York, NY: Appleton; 1892.
11. http://www.aimjournal.ir/pdffiles/32_12_12_0015.pdf
12. Packard, F.R. (1921). Life and Times of Ambroise Paré,
1510–1590. Paul B. Hoeber, New York.
13. https://en.wikipedia.org/wiki/Ambroise_Par%C3%A9
14. http://www.apimsf.org/default.aspx?id=33
15. 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).
16. 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.
17. http://www.psoriasiscouncil.org/docs/chapter_01.pdf
18. Charles Sanders Peirce & Joseph Jastrow (1885). Memoirs of the National Academy of
Sciences, 3, 73-83, Presented 17 October 1884.
19. http://psychclassics.yorku.ca/Peirce/small-diffs.htm
20. Biographical Memoirs of Fellows of the Royal Society of
London, 9: 91-120, (1963).
21. https://digital.library.adelaide.edu.au/dspace/bitstream/2440/15179/1/32.pdf
22. The J. Burns Amberson Lecture1, 2, American Review of Respiratory Disease, 90(4), pp. 505–515.
23. 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.
24. https://en.wikipedia.org/wiki/Nuremberg_trials
25. 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.
26. Annas GJ, Grodin MA, eds. The Nazi doctors and the Nuremberg
Code: human rights in human experimentation. New York: Oxford University Press,
1992.
27. 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
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
