Medical Research PDF

Medical research INTRODUCTION Medical research is aimed at understanding or treating a disease or health condition with the ultimate aim of improvement of human health or quality of life. The success of a research study is determined by the reliability and validity of its findings, and whether the...

Medical research INTRODUCTION Medical research is aimed at understanding or treating a disease or health condition with the ultimate aim of improvement of human health or quality of life. The success of a research study is determined by the reliability and validity of its findings, and whether the results can be generalised to the target population under consideration. Thus it is the choice of correct sample size and nature, or in other words the participation of representative patients or individuals, which is critical for good quality medical research. Medical research (or biomedical research), also known as health research, refers to the process of using scientific methods with the aim to produce knowledge about human diseases, the prevention and treatment of illness, and the promotion of health. Medical research encompasses a wide array of research, extending from "basic research" (also called bench science or bench research), – involving fundamental scientific principles that may apply to a preclinical understanding – to clinical research, which involves studies of people who may be subjects in clinical trials. Within this spectrum is applied research, or translational research, conducted to expand knowledge in the field of medicine. History The evolution of clinical research traverses a long and fascinating journey. The recorded history of clinical trials goes back to the biblical descriptions in 500 BC. The journey moves from dietary therapy – legumes and lemons – to drugs. After basic approach of clinical trial was described in 18th century, the efforts were made to refine the design and statistical aspects. These were followed by changes in regulatory and ethics milieu. This article captures the major milestones in the evolution of clinical trials. 562 BC - 1537: Pre-James Lind Era The world's first clinical trial is recorded in the “Book of Daniel” in The Bible. This experiment resembling a clinical trial was not conducted by a medical, but by King Nebuchadnezzar a resourceful military leader. 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. But several young 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. Avicenna (1025 AD) in his encyclopedic ‘Canon of Medicine’ describes some interesting rules for the testing of drugs. He suggests that in the clinical trial a remedy should be used in its natural state in disease without complications. He recommends that two cases of contrary types be studied and that study be made of the time of action and of the reproducibility of the effects. These rules suggest a contemporary approach for clinical trials. However, there seems to be no record of the application of these principles in practice. The first clinical 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. He describes,' at length my oil lacked and I was constrained to apply in its place a digestive made of yolks of eggs, oil of roses and turpentine. That night I could not sleep at any ease, fearing that by lack of cauterization I would find the wounded upon which I had not used the said oil dead from the poison. I raised myself 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’. However, it would take another 200 years before a planned controlled trial would be organized. 1747: James Lind and Scurvy Trial James Lind is considered the first physician to have conducted a controlled clinical trial of the modern era.1 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. His vivid description of the trial covers the essential elements of a controlled trial. Lind describes“”On the 20th of May 1747, I selected 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 the 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 light puddings, boiled biscuit with sugar, etc., and for supper, barley and raisins, rice and currants, sago and wine or the like. 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 … The 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. Next to the oranges, I thought the cyder had the best effects …” (Dr James Lind's “Treatise on Scurvy” published in Edinburgh in 1753). Although the results were clear, Lind hesitated to recommend the use of oranges and lemons because they were too expensive. It was nearly 50 years before 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. Lind's Treatise of 1953, was written while he was resident in Edinburgh and a Fellow of the Royal College of Physicians, contains not only his well known description of a controlled trial showing that oranges and lemons were dramatically better than the other treatments for the disease, but also a systematic review of previous literature on scurvy. 1800: Arrival of Placebo It 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. 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.” Evolution of Ethical and 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. The first International Guidance on the ethics of medical research involving subjects – the Nuremberg Code was formulated in 1947. Although informed consent for participation in research was described in 1900, the Nuremberg Code highlighted the essentiality of voluntariness of this consent. 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. In 1964 at 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. 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. In parallel to ethical guidelines, clinical trials started to become embodied in regulation as government authorities began recognizing a need for controlling medical therapies in the early 20th century. The FDA was founded in 1862 as a scientific institution and became a law enforcement organization after the US Congress passed the Food and Drugs Act in 1906. After that, legislation progressively demanded greater accountability for marketing food and drugs and the need for testing drugs in clinical trials increased. The regulatory and ethical milieu will continue to evolve as new scientific disciplines and technologies become part of drug development. Evolution of Clinical Trials in India India has recently been recognized as an attractive country for clinical trials. But the country's journey in clinical research field has a long history. India has a rich heritage of traditional medicine – Ayurveda. The classic ayurvedic texts contain detailed observations on diseases and in-depth guidance on remedies. It is likely that these descriptions are based on direct observations made by the ancient ayurveda experts. However, there is no recorded documentation in the ancient texts of any clinical experiments. Hence, one has to fall back on current history of medical research 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. At the 2nd meeting of the Governing Body in 1912, a historic decision was taken to start a journal for Indian Medical research. Between 1918--20, 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. The Central Ethical 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. Schedule Y of 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. The next major step has been revision of Schedule Y in Jan 2005. As compared to Schedule Y 1988, which had narrow and restrictive definitions of clinical trial phases, the amended Schedule Y 2005 provided pragmatic definitions for Phase I to IV. The definitions and guidelines for clinical trial phases are broad and rational. The earlier restrictions on number patients and centers in early phases stipulated in Schedule Y 1988 were removed allowing the sponsor company freedom to decide these in relation to protocol requirements. The phase lag requirements gave way to acceptance of concurrent Phase II-III as part of global clinical trials. Schedule Y 2005 legalized Indian GCP guidelines of 2001. This schedule stipulated GCP responsibilities of ethics committee (EC), investigator and sponsor and suggested formats for critical documents e.g. consent, report, EC approval, reporting of serious adverse event. These amendments in Schedule Y have been a major step forward in direction of GCP compliant trials and have provided the much-needed regulatory support to GCP guidelines. Since the Scurvy trial, clinical trials have evolved into a standardized procedure, focusing on scientific assessment of efficacy and guarding the patient safety. As the discipline of drug development is enriched by novel therapies and technologies, there will always be a continuing need to balance medical progress and patient safety. As the scientific advances continue to occur, there will be new ethical and regulatory challenges requiring dynamic updates in ethical and legal framework of clinical trials.