16 / 05 / 2016

The Long Journey of Clinical Trials: from James Lind’s Fair Test to Celebrating International Clinical Trials Day 2016

Taking the opportunity of the International Clinical Trials forthcoming celebration day, this article is our tribute to the long journey of Clinical Trials since 1700’s to the present date.

International Clinical Trials’ Day (ICTD) is celebrated worldwide on or near May 20 each year.

ICTD was first celebrated in 2005 in memory of James Lind, surgeon of Navy of Scotland who is believed to have conducted the first Clinical Trial in the Clinical Trials’ History.

James Lind, in his effort to treat the sailors of HMS Salisbury (a ship of the British Royal Navy) suffering from scurvy, initiated an experiment (“fair test”) on the 20th of May 1747 and thus prepared the grounds of current clinical trials’ environment.

What James Lind did, was to randomly group 12 sailors into sets of two and to administered to each set 6 different food supplements on a daily basis for a period of 14 days. Treatment food supplements consisted of the following ingredients:
1.1 litres of cider; twenty-five millilitres of elixir vitriol (dilute sulphuric acid); 18 millilitres of vinegar three times throughout the day before meals; half a pint of sea water; two oranges and one lemon continued for six days only (when the supply was exhausted); and a medicinal paste made up of garlic, mustard seed, dried radish root and gum myrrh.

As per Lind’s Report of his “fair” experiment, “the consequence was, that the most sudden visible good effects were perceived from the use of oranges and lemons;” …. “I am apt to think oranges preferable to think lemons, though perhaps both given together will be found most serviceable”.

This is considered to be the first randomized clinical trial with a specific design, and an experiment specific period. It is also evident that it includes characteristics of a controlled trial.

Even though no specific recommendation was issued at that time on the consumption of oranges and lemons (most likely due to their high cost back then), 50 years later, British Navy adopted the consumption of lemon juice as a compulsory part of the crews’ diet.

Almost a century later from Lind’s experiment, another benchmark is reached with the use of “placebo” for the first time in medical practice and clinical research.

As per Hooper’s Medical Dictionary of 1811, “placebo” is defined as “an epithet given to any medicine more to please than benefit the patient.”

However, the first actual use in practise of a “placebo” treatment was first introduced in 1863 by Austin Flint from USA who performed an experiment by comparing a dummy remedy to an active medication.

Flint conducted the experiment with 13 patients suffering from rheumatism by administering them an herbal extract and not a real medication. In 1886, he included a “Report” of his experiment in his book entitled “A Treatise on the Principles and Practice of Medicine” with these exact words confirming the success of placebo use: “The favourable progress of the cases was such as to secure for the remedy generally the entire confidence of the patients.”

The History of Clinical Research has also dark days to remember.
In 1932, during the period of Great Depression, the U.S. Public Health Service, sponsored a trial for the investigation of Syphilis during a time that no available treatment was in place. Even though the scientific grounds were justified, we cannot claim the same for the ethical soundness of the trial. This trial, actually entitled “Tuskegee Study of Untreated Syphilis in the Negro Male” recruited a very vulnerable population, African American impoverished males and not to mention under deceptive methods.
Most of the trial subjects were absolute unaware of their participation as trial participants and had no information on their health condition. One of most unethical aspects of this trial, was the withholding of the only medicine that would cure their disease: penicillin that was discovered and became the available treatment in 1947. As a result, many participants died, many wives were infected and many children were born with congenital syphilis disease.
It required a leakage to the press that eventually led to mass media wide publications, public outrage, condemnation of the entire situation and trial termination in 1972 (discovery date).
The disclosure of the circumstances under which the study was held and the exploitation of trial subjects are considered to be the foundations of the US National Research Act in 1974.

In 1943, during World War II time, Medical Research Council of UK, initiated the first and wide, including population throughout UK (recruiting over a thousand office and factory workers), double-blind, controlled trial to study the effect of patulin in the treatment of common cold.
To the disappointment of the Scientific world, the assessment of this trials’ results were of no positive outcome – patulin had not benefited the trial participants in any means.

A few years later, in 1947, Medical Research Council of UK, conducted the first trial with streptomycin. Streptomycin was discovered by US Scientists (with Waksman as leading scientist) in 1944 and was imported in UK (by UK Government) in 1946. This was the first randomized controlled trial of streptomycin in pulmonary tuberculosis. The trial involved a number of pioneer methods throughout its entire conduct, such as systematic enrolment criteria and x-ray assessment in a blinded manner (i.e. x-ray assessing scientists were blinded to patients’ treatment allocation), use of sealed envelopes with the treatment allocation, e.t.c. This streptomycin trial has been widely publicized and is commonly known as the “1948 watershed”.

The below cases derive from the most abhorrent period for Clinical Research and Humanity. During World War II, Nazi physicians conducted experiments on imprisoned human subjects including children, in occupation camps. The nature and intervention of those experiments was so severe, hazardous and torturous that in most cases led to death, injury, permanent disability and even deformations (e.g. mutilations) and mental diseases to many of the subjects who survived those experiments.

With the aim to develop new weapons, to aid the recovery of German soldiers during war conditions and related injuries, to support their hypothesis of superiority of “Aryan race” and to “cure homosexuality”, Nazi physicians conducted a number of repulsive experiments, such as:

* Bone, muscle, and nerve transplantation experiments (most of the times without the use of anaesthesia)
* Head injury experiments (subject suffered series of hits to the head with a mechanical hammer within seconds)
* Freezing experiments (aiming to treat hypothermia, Nazi placed subjects to cold water to evaluate resistance to cold water – the experiment led many subjects to death)
* Malaria experiments (subjects injected with infected mosquitos – half of them died)
* Experiments on twins (one of the experiments included injections to the eyes of the twins with different dyes to assess if a change to the colour of the eyes would occur)
* Immunization experiments
* Mustard gas experiments (subjects suffered chemical burns)
* Sulfonamide experiments
* Sea water experiments (administering subjects with nothing but sea water)
* Sterilization experiments (via radiation techniques subjects were left sterile and with severe radiation burns)
* Experiments with poison (most of the subjects died with poisons or were executed directly after poison administration so the physicians could conduct autopsies)
* Incendiary bomb experiments
* Blood coagulation experiments
* Typhus (“spotted fever”) and other vaccine experiments
The Nazi physicians who participated in those trials were prosecuted and most of them found guilty during the well-known “Doctor’s Trial” of Nuremberg (1946-1947).

The reveal of those hideous, torturous, unspeakable crimes to imprisoned subjects and general inhuman acts, emerged the need for setting rules and principles for the protection of the rights, well-being and dignity of humans, subjects to experiments. “Doctors Trial”, resulted in the constitution of a set of ethical principles that should apply during the conduct of experiments with human subjects. This set of ethical principles, form the Nuremberg Code (1947). We herewith list the main aspects of Nuremberg’s Code –the Decalogue of Nuremberg Code:

1. The voluntary consent of the human subject is absolutely essential. This means that the person involved should have legal capacity to give consent; should be so situated as to be able to exercise free power of choice, without the intervention of any element of force, fraud, deceit, duress, overreaching, or other ulterior form of constraint or coercion; and should have sufficient knowledge and comprehension of the elements of the subject matter involved as to enable him to make an understanding and enlightened decision. This latter element requires that before the acceptance of an affirmative decision by the experimental subject there should be made known to him the nature, duration, and purpose of the experiment; the method and means by which it is to be conducted; all inconveniences and hazards reasonably to be expected; and the effects upon his health or person which may possibly come from his participation in the experiment.
The duty and responsibility for ascertaining the quality of the consent rests upon each individual who initiates, directs, or engages in the experiment. It is a personal duty and responsibility which may not be delegated to another with impunity.
2. The experiment should be such as to yield fruitful results for the good of society, unprocurable by other methods or means of study, and not random and unnecessary in nature.
3. The experiment should be so designed and based on the results of animal experimentation and a knowledge of the natural history of the disease or other problem under study that the anticipated results justify the performance of the experiment.
4. The experiment should be so conducted as to avoid all unnecessary physical and mental suffering and injury.
5. No experiment should be conducted where there is an a priori reason to believe that death or disabling injury will occur; except, perhaps, in those experiments where the experimental physicians also serve as subjects.
6. The degree of risk to be taken should never exceed that determined by the humanitarian importance of the problem to be solved by the experiment.
7. Proper preparations should be made and adequate facilities provided to protect the experimental subject against even remote possibilities of injury, disability or death.
8. The experiment should be conducted only by scientifically qualified persons. The highest degree of skill and care should be required through all stages of the experiment of those who conduct or engage in the experiment.
9. During the course of the experiment the human subject should be at liberty to bring the experiment to an end if he has reached the physical or mental state where continuation of the experiment seems to him to be impossible.
10. During the course of the experiment the scientist in charge must be prepared to terminate the experiment at any stage, if he has probable cause to believe, in the exercise of the good faith, superior skill and careful judgment required of him, that a continuation of the experiment is likely to result in injury, disability, or death to the experimental subject.

It is obvious that all available ethical standards, guidelines, regulations and rules for the appropriate conduct of Clinical Trials have their origin in the above principles.

Yet, Tribute should be paid to Hippocratic Oath as the Source of any current and future Ethical Code for the conduct of Clinical Practice and Clinical Research.

Understanding, Maintaining, Respecting, Fostering and Promoting Ethics should be the innate duty of each Health Care Professional involved in Clinical Research.

The Journey of Clinical Trials goes on with the Discovery of Novel Medications and Curing of Lethal Diseases, Treating of Rare Diseases, Curing and Treating Neglected Tropical Diseases.

Ethical Principals such as the Guidelines for Good Clinical Practise, Rules, Regulations (e.g. Clinical Trials Directive and Regulation) and Guidelines for the Conduct of Clinical Research, are on an ongoing update, optimization and empowerment so as the Highest Standards are met for the assurance of Subjects’ Dignity, Rights, Well-being and the research’s Scientific Value and Credibility.

As the awareness and involvement of the trials’ participants is increased and clinical data information becomes now publically accessible, confidence and trust to clinical research is strengthened.

We are reaching a new ERA that Clinical Research Community goes along together with the Public, the support of the Regulations, and the Protection that Highest Ethical standards assure towards, global well-being and science excellence.

– The James Lind Library (http://www.jameslindlibrary.org/)
– ECRIN – European Clinical Research Infrastructure Network announcement (http://www.ecrin.org)
– ACRP – Association of Clinical Research Professionals announcement (http://www.acrpnet.org)
– British Medical Journal, A Medical Research Council Investigation, “Streptomycin Treatment of Pulmonary Tuberculosis”, London, Saturday October 30 1948
– The Nuremberg Code (1947), BRITISH MEDICAL JOURNAL No 7070 Volume 313: Page 1448, 7 December 1996
– Harvard, Law School Library, Nuremberg’s Trial Project
– The University of Alabama, Research Compliance (brief history of the events that contributed to the development of research regulations and ethics rules)
– Tuskegee University: About the USPHS Syphilis Study