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Historical evolution of clinical trial guidelines in the world
The document summarizes the historical evolution of clinical trial guidelines from ancient times to the present. Some key events include the first recorded clinical trial by King Nebuchadnezzar in 562 BC, James Lind's 1757 controlled trial of treatments for scurvy, the introduction of the placebo concept in the 1800s, the first double-blind randomized controlled trial in 1943 investigating treatment for the common cold, and major milestones in the development of ethical guidelines and regulations for clinical trials over the 20th century including the Nuremberg Code, Declaration of Helsinki, and establishment of regulatory bodies like the ICMR in India.
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Historical evolution of clinical trial guidelines in the world
- 1. Historical Evolution of ClinicalTrial Guidelines in the World Presented by: Bhagyashree Srivastava BT 4th year.
- 2. 562 BC -1537: Pre-James Lind Era • “Book of Daniel” – First clinical trial • clinical trial was not conducted by a medical, but by King Nebuchadnezzar. During his rule in Babylon, Nebuchadnezzar ordered his people to eat only meat and drink only wine, a diet he believed would keep them in sound physical condition.
- 3. • But severalyoung men of royal blood, who preferred to eat vegetables, objected. • The king allowed these rebels to follow a diet of legumes and water — but only for 10 days. • When Nebuchadnezzar's experiment ended, the vegetarians appeared better nourished than the meat-eaters, so the king permitted the legume lovers to continue their diet. • This probably was the one of the first times in evolution of human species that an open uncontrolled human experiment guided a decision about public health.
- 4. • The firstclinical trial of a novel therapy was conducted accidentally by the famous surgeon Ambroise Pare in 1537. • In 1537 while serving with the Mareschal de Motegni he was responsible for the treatment of the battlefield wounded soldiers. • As the number of wounded was high and the supply of conventional treatment – oil was not adequate to treat all the wounded, he had to resort to unconventional treatment.
- 5. 1747: James Lindand Scurvy Trial • “Treatise on Scurvy” • James Lind is considered the first physician to have conducted a controlled clinical trial of the modern era. • Dr Lind (1716-94), whilst working as a surgeon on a ship, was appalled by the high mortality of scurvy amongst the sailors. • He planned a comparative trial of the most promising cure for scurvy.
- 6. • selected twelvepatients in the scurvy • all in general had putrid gums, the spots and lassitude, with weakness of the knees. • lay together in one place, being a proper apartment for the sick in the fore-hold; and had one diet common to all • Two were ordered each a quart of cyder a day. Two others took twenty-five drops of elixir vitriol three times a day … Two others took two spoonfuls of vinegar three times a day … Two of the worst patients were put on a course of sea-water … Two others had each two oranges and one lemon given them every day … The two remaining patients, took … an electary recommended by a hospital surgeon
- 7. • consequence was,that 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 other was the best recovered of any in his condition; and was appointed to attend the rest of the sick
- 8. 1800: Arrival ofPlacebo • took another century before the emergence of another important mile stone in the history of modern clinical trial: the placebo. • The word placebo first appeared in medical literature in the early 1800s. • Hooper's Medical Dictionary of 1811 defined it as “an epithet given to any medicine more to please than benefit the patient.” However, it was only in 1863 that United States physician Austin Flint planned the first clinical study comparing a dummy remedy to an active treatment. • He treated 13 patients suffering from rheumatism with an herbal extract which was advised instead of an established remedy.
- 9. • In 1886,Flint described the study in his book A Treatise on the Principles and Practice of Medicine. “This was given regularly, and became well known in my wards as the ‘placeboic remedy’ for rheumatism. The favorable progress of the cases was such as to secure for the remedy generally the entire confidence of the patients.”
- 10. 1943: The FirstDouble blind Controlled Trial - Patulin for Common Cold • The Medical Research Council (MRC) UK carried out a trial in 1943-4 to investigate patulin treatment for (an extract of Penicillium patulinum) the common cold. • This was the first double blind comparative trial with concurrent controls in the general population in recent times. • It was one of the last trial with non-randomized or quasi- randomized allocation of subjects. • The MRC Patulin Clinical Trials Committee (1943) was chaired by Sir Harold Himsworth, and its statisticians were M Greenwood and W J Martin. • This nationwide study enrolled over a thousand British office and factory workers suffering from colds.
- 11. • The studywas rigorously controlled by keeping the physician and the patient blinded to the treatment. • The treatment allocation was done using an alternation procedure. • A nurse allocated the treatment in strict rotation in a separate room. • The nurse filed the record counterfoil separately, and detached the code label for the appropriate bottle before asking the patient to visit the doctor. • The statisticians considered this an effective random concurrent allocation. • However, the outcome of the trial was disappointing as the analysis of trial data did not show any protective effect of patulin.
- 12. Evolution of Ethicaland Regulatory Framework • The ethical framework for human subject protection has its origins in the ancient Hippocratic Oath, which specified a prime duty of a physician – to avoid harming the patient. However, this oath was not much respected in human experimentation and most advances in protection for human subjects have been a response to human abuses e.g. World War II experiments.
- 13. • The firstInternational Guidance on the ethics of medical research involving subjects – the Nuremberg Code was formulated in 1947 • In 1948, Universal Declaration of Human Rights (adopted by the General Assembly of the United Nations) expressed concern about rights of human beings being subjected to involuntary maltreatment. • The brush with thalidomide tragedy helped the U.S. pass the 1962 Kefauver-Harris amendments, which strengthened federal oversight of drug testing and included a requirement for informed consent.
- 14. • In 1964at Helsinki, the World Medical Association articulated general principles and specific guidelines on use of human subjects in medical research, known as the Helsinki Declaration. • The Helsinki Declaration has been undergoing changes every few years the last one being in 2008. • However, the use of placebo and post-trial access continue to be debatable issues.
- 15. • In 1966,the International Covenant on Civil and Political Rights specifically stated, ‘No one shall be subjected to torture or to cruel, inhuman or degrading treatment or punishment. In particular, no one shall be subjected without his consent to medical or scientific treatment.’ • Dr. Henry Beecher's 1966 study of abuses and the discovery of human exploitation of Tuskegee study in the 1970s reinforced the call for tighter regulation of government funded human research. • The US National Research Act of 1974 and Belmont Report of 1979 were major efforts in shaping ethics of human experimentation. • In 1996, International Conference on Harmonization published Good Clinical Practice, which has become the universal standard for ethical conduct of clinical trials.
- 16. Evolution of ClinicalTrials in India • The major historic milestones of the Indian Council of Medical Research reflect, in many ways, the growth and development of medical research in the country over the last nine decades. • First meeting of the Governing Body of the Indian Research Fund Association (IRFA) was held on November 15, 1911 at the Plague Laboratory, Bombay, under the Chairmanship of Sir Harcourt Butler.
- 17. • a journalfor Indian Medical research. Between 1918—20 started • Several projects on beriberi, malaria, kala azar and indigenous drugs were initiated. In 1945, a Clinical Research Unit – the first research unit of IRFA attached to a medical institution- was established at the Indian Cancer Research Centre, Bombay. In 1949 • IRFA was redesignated as the Indian Council of Medical Research. • Over next 60 years, ICMR established many national research centers in the fields of nutrition, tuberculosis, leprosy, viral disease, cholera, enteric disease, reproductive disorders, toxicology, cancer, traditional medicine, gas disaster, genetics, AIDS etc
- 18. • The CentralEthical Committee of ICMR on Human Research constituted under the Chairmanship of Hon'ble Justice (Retired) M.N. Venkatachaliah held its first meeting on September 10, 1996. • Several subcommittees were constituted to consider ethical issues in specific areas e.g., Epidemiological Research; Clinical Evaluation of Products to be used on Humans; Organ Transplantation; Human Genetics, etc. • The committee released Ethical Guidelines for Biomedical Research on Human Participants in 2000 which were revised in 2006
- 19. • Schedule Yof Drugs and Cosmetics Act came into force in 1988 and established the regulatory guidelines for clinical trial (CT) permission. • The schedule did force the industry to conduct Phase III clinical trials for registration of a new drug and supported growth of a predominantly generic Indian pharmaceutical industry. • However, this schedule only permitted clinical trials at a phase lower than its global status. • This phase lag obstructed integration of India in global clinical development.