ICH-GCP_E6_Gudelines_Section 1_History_Principles & Background of GCP.pptx

ICH

1. Foundation Course An introduction,origin,History of clinical trials 1

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3. History of GCP 3

4. History of GCP (cont..) The concept of the ‘good physician‘ dates back to the ancient world and it is evidenced by the Hippocratic Oath (460 BC).  4

5. History of GCP (cont..) In the United States, the first landmark in the regulation of drugs was the Food and Drugs Act of 1906.  It is considered to be the result of very dangerous and even deadly drugs that could have been sold legally just like any other medical goods. For example, such drugs were ‘Grandma’s Secret’ and ‘Kopp’s Baby’s Friend’, which contained a huge amount of morphine. ‘ Dr. King’s Consumption Cure’ and ‘ Dr. Bull’s Cough Syrup‘ are examples of drugs which had large doses of morphine and chloroform as well. 5

6. Have you ever wondered what clinical trials are and how they are conducted? This web seminar is designed to answer those basic questions. We will look at how drugs progress from discovery to testing in humans, and learn what it takes to obtain approval to treat a disease or condition. we will review how Good Clinical Practice (GCP) is applied to clinical trials around the world and how it is designed to protect clinical trial participants and ensure that the information obtained during a clinical trial is accurate and reliable. 6

7. James lind In 1747,  the first ever  clinical trial ,  he developed the theory that  citrus fruits  cured  scurvy . 7

8. Scurvy  is a disease resulting from a lack of vitamin C (ascorbic acid). Early symptoms of deficiency include weakness, feeling tired and sore arms and legs. Without treatment, decreased red blood cells, gum disease, changes to hair, and bleeding from the skin may occur. Other names:  Moeller's disease, Cheadle's dis... Symptoms:  Weakness, feeling tired, changes to ... Treatment:  Vitamin C supplements, Citrus fruits Causes:  Lack of  vitamin C 8

9. 9 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. His vivid description of the trial covers the essential elements of a controlled trial . For 18th Century sailors, disease during long sea voyages was often more dangerous than enemy action. James Lind is described by the Royal Navy as "the father of naval medicine"

10. This brings us to James Lind and his scurvy “clinical trial”. The year is 1747 and Lind, a surgeon on a ship decides to test out the most promising cures for scurvy, describing a process closely resembling our modern day controlled clinical trials. He chose a group of similar cases on one and the same diet and gave different medicine in pairs – cider, vitriol, vinegar, sea water, oranges, and lemons. Of course, as you know, the oranges and lemons “won” with the cider following closely but here’s what happened next: oranges were far too expensive to be recommended as treatment despite the high levels of mortality. It was another 50 years before the British Navy supplied every overseas journey with lemon juice and even then the lemons were eventually replaced by the much cheaper at that time limes. 10

11. 11 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). In 1747, on board HMS Salisbury, he carried out one of the first controlled clinical trials recorded in medical science.

12. 12 He took 12 men suffering from similar symptoms of scurvy, divided them into six pairs and treated them with remedies suggested by previous writers: a quart of cider a day 25 drops of elixir of vitriol, three times a day half a pint of sea-water a day a nutmeg-sized paste of garlic, mustard seed, horse-radish, balsam of Peru, and gum myrrh three times a day two spoonfuls of vinegar, three times a day two oranges and one lemon a day By the end of the week, those on citrus fruits were well enough to nurse the others. However, in the Royal Navy, Dr Lind is remembered as a hero. In summary, the history of scurvy in the British Navy during the second half of the 18th century shows how comparative clinical trials in controlled conditions of time and environment were well described by Lind, yet, initially for understandable reasons, imperfectly translated into practice, and only on a very small scale. James Lind is remembered as the man who helped to conquer a killer disease. His reported experiment on board a naval ship in 1747 showed that oranges and lemons were a cure for scurvy.  

13. The Tuskegee experiment began in 1932, at a time when there was no known treatment for syphilis. After being recruited by the promise of free medical care, 600 men originally were enrolled in the project for free medical care and treatment instead it was a secret study to study the impact and progress of syphilis ( Syphilis  is a bacterial infection usually spread by sexual contact. The disease starts as a painless sore — typically on your genitals, rectum or mouth.  Syphilis  spreads from person to person via skin or mucous membrane contact with these sores)on human body The participants were primarily sharecroppers, and many had never before visited a doctor. Doctors from the U.S. Public Health Service (PHS), which was running the study, informed the participants—399 men with latent syphilis and a control group of 201 others who were free of the disease—they were being treated for bad blood, a term commonly used in the area at the time to refer to a variety of ailments.and diseases The men were monitored by health workers but only given placebos such as aspirin and mineral supplements, despite the fact penicillin became the recommended treatment for syphilis in 1947. PHS researchers convinced local physicians in Macon County not to treat the participants, and research was done at the Tuskegee Institute. (Now called Tuskegee University, the school was founded in 1881 with Booker T. Washington at its first teacher.) 13 Tuskegee Syphilis Study (1932)

14. In 1932, the USPHS, working with the Tuskegee Institute, began a study to record the natural history of syphilis. It was originally called the “Tuskegee Study of Untreated Syphilis in the Negro Male” (now referred to as the “USPHS Syphilis Study at Tuskegee”). The study initially involved 600 Black men – 399 with syphilis, 201 who did not have the disease. Participants’ informed consent was not collected. Researchers told the men they were being treated for “bad blood,” a local term used to describe several ailments, including syphilis, anemia, and fatigue. In exchange for taking part in the study, the men received free medical exams, free meals, and burial insurance In order to track the disease’s full progression, researchers provided no effective care as the men died, went blind or insane or experienced other severe health problems due to their untreated syphilis. In the mid-1960s, a PHS venereal disease investigator in San Francisco named Peter Buxton found out about the Tuskegee study and expressed his concerns to his superiors that it was unethical. In response, PHS officials formed a committee to review the study but ultimately opted to continue it, with the goal of tracking the participants until all had died, autopsies were performed and the project data could be analyzed. 14

15. 15 In 1972, an  Associated Press story external icon about the study was published As a result, the story wasv leaked to a reporter friend, who passed it on to a fellow reporter, Jean Heller of the Associated Press. Heller broke the story in July 1972, prompting public outrage and forcing the study to shut down. In October 1972, the panel advised stopping the study. A month later, the Assistant Secretary for Health and Scientific Affairs  announced the end external icon of the study. By that time, 28 participants had perished from syphilis, 100 more had passed away from related complications, at least 40 spouses had been diagnosed with it and the disease had been passed to 19 children at birth. Later in 1973, a class-action lawsuit was filed on behalf of the study participants and their families, resulting in a $10 million, out-of-court settlement in 1974. On May 16, 1997, President Bill Clinton issued a  formal Presidential Apology external icon for the study. Tuskegee Syphilis Study (1932)

16. Outcome of Tuskegee Syphilis Study Men involved had agreed freely to be examined & treated. There was no evidence that researchers had informed them of the study or its real purpose. In fact, the men had been misled and had not been given all the facts required to provide informed consent. The men were never given adequate treatment for their disease. Even when penicillin became the drug of choice for syphilis in 1947 1973 -Congress holds hearings and a class-action lawsuit is filed on behalf of the study participants. A $10 million out-of-court settlement is reached. 16

17. 17 Sulfanilamide , a drug used to treat streptococcal infections, had been shown to have dramatic curative effects and had been used safely for some time in tablet and powder form. Elixir sulfanilamide  was an improperly prepared  sulfanilamide   medicine that caused mass  poisoning  in the United States in 1937. It caused the deaths of more than 100 people. The public outcry caused by this incident and other similar disasters led to the passing of the 1938  Federal Food, Drug, and Cosmetic Act , which significantly increased the  Food and Drug Administration 's powers to regulate drugs In 1937,  S.E Massengill Company , a pharmaceutical manufacturer, created a preparation of  sulfanilamide  using  diethylene glycol  (DEG) as a  solvent , and called the preparation "Elixir Sulfanilamide ". [3]  DEG is poisonous to humans and other mammals, but Harold Watkins, the company's chief pharmacist and chemist, was not aware of this. (Though the first case of a fatality from ethylene glycol occurred in 1930 and studies had been published in medical journals stating DEG could cause kidney damage or failure, its toxicity was not widely known prior to the incident.) [ Watkins simply added raspberry flavoring to the sulfa drug which he had dissolved in DEG and the company S.E Massengill then marketed the product.  Animal testing  was not required by law, and Massengill performed none; there were no regulations requiring premarket safety testing of new drugs. The company started selling and distributing the medication in September 1937. By October 11, the  American Medical Association  received a report of several deaths caused by the medication. The  Food and Drug Administration  was notified, and an extensive search was conducted to recover the distributed medicine. [5]   Frances Oldham Kelsey  assisted on a research project that verified that the  excipient  DEG was responsible for the fatal  adverse effects . At least 100 deaths were blamed on the medication. Elixir Sulfanilamide disaster_1937

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19. Elixir Sulfanilamide disaster_1937 T he US Food and Drug Administration’s role in the regulation of novel medicines was born out of tragedy. Seventy-one adults and 34 children died in the fall of 1937 after taking a drug called Elixir Sulfanilamide to treat a variety of ailments, from gonorrhea to sore throat. At that time, the FDA, which had been launched in 1906 as the Bureau of Chemistry, served simply to police claims made about food and drug ingredients. No formal government approval was required to market new drugs. The disaster provoked a public outcry that led to the passage of the 1938 Food, Drug, and Cosmetics Act, which gave the FDA power to monitor the safety of new drugs. That all changed in 1938, after the deaths linked to Elixir Sulfanilamide had become a national scandal 19

20. Food, Drug, and Cosmetic Act (1938) which required companies to perform animal safety tests on their proposed new drugs and submit the data to the FDA before being allowed to market their products. The  Federal Food ,  Drug, and Cosmetic Act  was passed by Congress in  1938  in reaction to the growing public safety demands. The primary goal of the  Act  is to protect the health and safety of the public by preventing deleterious, adulterated or misbranded articles from entering interstate commerce. The United States  Federal Food, Drug, and Cosmetic Act  (abbreviated as  FFDCA ,  FDCA , or  FD&C ), is a set of laws passed by  Congress  in 1938 giving authority to the U.S.  Food and Drug Administration  (FDA) to oversee the  safety of food , drugs, medical devices, and cosmetics. The introduction of this act was influenced by the death of more than 100 patients due to a  sulfanilamide  medication where  diethylene glycol  was used to dissolve the drug and make a liquid form [4]  (see  elixir sulfanilamide disaster ). It replaced the earlier  Pure Food and Drug Act  of 1906. 20

21. History-Nuremberg trial and code The Code was formulated 50 years ago, in August 1947, in Nuremberg, Germany, by American judges sitting in judgment of Nazi doctors accused of conducting murderous and torturous human experiments in the concentration camps (the so-called Doctors' Trial). During the Second World War a number of severe unethical experiments were carried out by researchers affiliated with the Nazi party in Germany. Patients with a physical and/or mental disability and prisoners of war were forcibly experimented upon to gather information about racial characteristics and genetics. These experiments were investigated, and the doctors prosecuted in the Nuremberg Trials and, more specifically, the Doctor Trials which began in 1947 . A victim of a Nazi medical experiment is immersed in icy water to test reactions to hyperthermia. SS doctor Sigmund Rancher oversees the experiment . The  Nuremberg trials  ( German :  Nürnberger Prozesse ) were a series of  military tribunals  held after  World War II  by the  Allied forces  under  international law  and the  laws of war . The trials were most notable for the prosecution of prominent members of the political, military, judicial, and economic leadership of  Nazi Germany , who planned, carried out, or otherwise participated in  the Holocaust  and other  war crimes . The trials were held in  Nuremberg , Germany, and their decisions marked a turning point between classical and contemporary international law. 21

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23. Nuremberg Code Held for the purpose of bringing Nazi war criminals to justice, the Nuremberg trials were a series of 13 trials carried out in Nuremberg, Germany, between 1945 and 1949. The defendants, who included Nazi Party officials and high-ranking military officers along with German industrialists, lawyers and doctors, were indicted on such charges as crimes against peace and crimes against humanity. Nazi leader Adolf Hitler (1889-1945) committed suicide and was never brought to trial. On December 9, 1946, an American military tribunal opened criminal proceedings against 23 leading German physicians and administrators for their willing participation in war crimes and crimes against humanity. This case is known as the  "Doctors Trial"   (USA v. Karl Brandt et. al). On August 19, 1947, the judges of the tribunal delivered their verdict. But before announcing the guilt or innocence of each defendant, they confronted the difficult question of medical experimentation on human beings. Several German doctors had argued in their own defense that their experiments differed little from those conducted before the war by German and American scientists. Furthermore they showed that no international law or informal statement differentiated between legal and illegal human experimentation. This argument was a great concern to two US doctors who had worked with the prosecution during the trial, Dr.  Andrew Ivy and Dr. Leo Alexander. As a result, on April 17, 1947, Dr. Alexander submitted a memorandum to the United States Counsel for War Crimes. The memo outlined six points that defined legitimate medical research. The trial's verdict of August 19 reiterated almost all of these points in a section entitled "Permissible Medical Experiments." It also revised the original six points into ten, and these the ten points became known as the "Nuremberg Code." 23

24. NUREMBERG CODE In 1947, the Nuremberg Code was created as a result of the unethical and horrific experiments carried out during World War II at Nazi war camps by German physicians, who were subsequently tried and charged at the Nuremberg Military Tribunal. This code states the need for a scientific basis in research on human subjects and voluntary consent and protection of participants. The  Nuremberg Code  ( German :  Nürnberger Kodex ) is a set of  research ethics  principles for  human experimentation  created as a result of the  Nuremberg trials  at the end of the  Second World War . The  Code  was formulated 50 years ago, in August 1947, in  Nuremberg , Germany, by American judges sitting in judgment of Nazi doctors accused of conducting murderous and torturous human experiments in the concentration camps (the so-called Doctors' Trial). 24

25. NUREMBERG CODE The voluntary consent of the human subject is absolutely essential. 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. 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 will justify the performance of the experiment. The experiment should be so conducted as to avoid all unnecessary physical and mental suffering and injury. 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. 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.. Proper preparations should be made and adequate facilities provided to protect the experimental subject against even remote possibilities of injury, disability, or death. 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. 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. 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 . 25

26. Universal Declaration of Human Rights The Universal Declaration of Human Rights is a historic document which outlined the rights and freedoms everyone is entitled to. It was the first international agreement on the basic principles of human rights. It laid the  foundation  for the human rights protections that we have in the UK today. The Universal Declaration of Human Rights, which was adopted by the  UN General Assembly  on 10 December 1948, was the result of the experience of the Second World War. The  Universal Declaration  includes civil and political  rights , like the  right  to life, liberty, free speech and privacy. It also includes economic, social and cultural  rights , like the  right  to social security, health and education. 26

27. Thalidomide disaster_1962 The Thalidomide disaster is one of the darkest episodes in pharmaceutical research history. The drug was marketed as a mild sleeping pill safe even for pregnant women. However, it caused thousands of babies worldwide to be born with malformed limbs. The damage was revealed in 1962. Many children in the 1960's, like the kindergartner pictured above, were born with phocomelia as a side effect of the drug thalidomide, resulting in the shortening or absence of limbs . Thalidomide first entered the German market in 1957 as an over-the-counter remedy, based on the maker’s safety claims. They advertised their product as “completely safe” for everyone, including mother and child, “even during pregnancy,” as its developers “could not find a dose high enough to kill a rat.” By 1960, thalidomide was marketed in 46 countries, with sales nearly matching those of aspirin. 27

28. The Thalidomide disaster is one of the tragic events which happened in the history of medical research field. This disaster resulted in the rules becoming more stringent for the pharmaceutical industries Initially, Thalidomide drug was marketed as a mild sleeping pill. Later, it was found that Thalidomide could also be used safely against nausea. And hence, healthcare professionals started prescribing the drug to pregnant women to relief them from morning sickness symptom. Thalidomide was widely used in late 1950s and early 1960s. However, the drug caused unexpected and serious damage to thousands of unborn babies worldwide. The consumption of drug by pregnant women during pregnancy (especially first four to eight weeks) lead to birth of babies with birth defects such as deafness, blindness, disfigurement, cleft palate, phocomelia (bilateral shortened limbs) and other defects. It even caused deaths of many. Babies affected by this disaster were called “Thalidomide Babies”. The whole damage was noticed in 1960s post which the drug Thalidomide was banned immediately. 28

29. Kefauver Harris Amendment (1962) by US congress "Drug Efficacy Amendment"   The Kefauver Harris Amendment strengthened the U.S. Food and Drug Administration's control of experimentation on humans and changed the way new drugs are approved and regulated. Before the Thalidomide scandal in Europe, and Canada, U.S. drug companies only had to show their new products were safe. The amendment was a response to the  Thalidomide  tragedy. It introduced a "proof-of-efficacy" requirement, that was not present before. In addition, the Amendment required drug advertising to disclose accurate information about side effects and efficacy of treatments. Finally, cheap generic drugs could no longer be marketed as expensive drugs under new trade names as new "breakthrough" medications, as they were prior to the amendment. It introduced a requirement for drug manufacturers to provide proof of the effectiveness and safety of their drugs before approval, It is required for drug advertising to disclose accurate information about side effects, and stopped cheap generic drugs being marketed as expensive drugs under new trade names as new "breakthrough" medications. The U.S. Supreme Court determined that generic drugs are new drugs . The efficacy requirement was applied to drugs marketed between 1906 and 1962. ... The FDA will approve the product as GRASE (generally recognized as safe and effective) and not a new drug. 29

30. Declaration of Helsinki_1964 The  Declaration of Helsinki  was adopted in  1964  by the 18th WMA General Assembly, at  Helsinki . This is a set of ethical principles regarding human experimentation developed for the medical community by the World Medical Association (WMA). It is widely regarded as the cornerstone document on human research ethics. Declaration of Helsinki, formal statement of ethical principles published by the World Medical Association (WMA) to guide the protection of human participants in medical research. The 2013 version of the Declaration of Helsinki is the only one that is officially recognized by the World Medical Association; all of the prior versions were replaced by the 2013 versions and they should only be used for historical purposes. The World Medical Association's  Declaration of Helsinki was  first adopted in 1964. In its 40-year lifetime the  Declaration has been revised  five times and  has  risen to a position of prominence as a guiding statement of ethical principles for doctors involved in medical research. “ The World Medical Association has developed the Declaration of Helsinki as a statement of ethical principles to provide guidance to physicians and other participants in medical research involving human subjects. It is the duty of the physician to promote and safeguard the health of the people. The physician’s knowledge and conscience are dedicated to the fulfilment of this duty ” 30

31. The health of my patient will be my first consideration,” and the International Code of Medical Ethics declares that, “A physician shall act in the patient’s best interest when providing medical care.”   It is the duty of the physician to promote and safeguard the health, well-being and rights of patients, including those who are involved in medical research. The physician’s knowledge and conscience are dedicated to the fulfilment of this duty.         Medical progress is based on research that ultimately must include studies involving human subjects.         The primary purpose of medical research involving human subjects is to understand the causes, development and effects of diseases and improve preventive, diagnostic and therapeutic interventions (methods, procedures and treatments). Even the best proven interventions must be evaluated continually through research for their safety, effectiveness, efficiency, accessibility and quality.    Medical research is subject to ethical standards that promote and ensure respect for all human subjects and protect their health and rights.   While the primary purpose of medical research is to generate new knowledge, this goal can never take precedence over the rights and interests of individual research subjects.   It is the duty of physicians who are involved in medical research to protect the life, health, dignity, integrity, right to self-determination, privacy, and confidentiality of personal information of research subjects. The responsibility for the protection of research subjects must always rest with the physician or other health care professionals and never with the research subjects, even though they have given consent. 31

32. Physicians must consider the ethical, legal and regulatory norms and standards for research involving human subjects in their own countries as well as applicable international norms and standards. No national or international ethical, legal or regulatory requirement should reduce or eliminate any of the protections for research subjects set forth in this Declaration. Medical research should be conducted in a manner that minimises possible harm to the environment.     Medical research involving human subjects must be conducted only by individuals with the appropriate ethics and scientific education, training and qualifications. Research on patients or healthy volunteers requires the supervision of a competent and appropriately qualified physician or other health care professional.   Groups that are underrepresented in medical research should be provided appropriate access to participation in research. Physicians who combine medical research with medical care should involve their patients in research only to the extent that this is justified by its potential preventive, diagnostic or therapeutic value and if the physician has good reason to believe that participation in the research study will not adversely affect the health of the patients who serve as research subjects.    Appropriate compensation and treatment for subjects who are harmed as a result of participating in research must be ensured. 32

33. WHO_1968 & 1975 The World Health Organization (WHO) plays an essential role in the global governance of health and disease; due to its core global functions of  establishing, monitoring and enforcing international norms and standards , and coordinating multiple actors toward common goals. It is responsible for  providing leadership on global health matters , shaping the health research agenda, setting norms and standards, articulating evidence-based policy options, providing technical support to countries and monitoring and assessing health trends. WHO’s International Clinical Trials Registry Platform (ICTRP) links clinical trials registers globally in order to ensure a single point of access and the unambiguous identification of trials with a view to enhancing access to information by patients, families, patient groups and others. The ICTRP is a global initiative that aims to make information about all clinical trials involving humans publicly available. It also aims to: improve the comprehensiveness, completeness and accuracy of registered clinical trial data; communicate and raise awareness of the need to register clinical trials; ensure the accessibility of registered data; build capacity for clinical trial registration; encourage the utilization of registered data; and ensure the sustainability of the ICTRP. 33

34. Belmont report_1979 Belmont Report was issued in April 1979 by the National Commission for Protection of Human Subjects of Biomedical and Behavioral Research. The Belmont Report marks an important milestone in the history of clinical research. It established guidelines for basic ethical principles, as well as informed consent, the assessment of risks and benefits and subject selection. The report was issued on 30 September 1978 .  and published in the Federal Register on 18 April 1979. The report took its name from the Belmont Conference Center where the document was drafted in part.  The Belmont Report  attempts to summarize the basic ethical principles identified by the Commission  in the course of its deliberations. ... It is a statement of basic ethical principles and guidelines that should assist in resolving the ethical problems that surround the conduct of research with human subjects. The Belmont Report is one of the leading works concerning ethics and health care research. Its primary purpose is  to protect subjects and participants in clinical trials or research studies . This report consists of 3 principles: beneficence, justice, and respect for persons. The principles of BELMONT report are as follows: Respect for Persons : This principle acknowledges the dignity and freedom of every person. It requires obtaining informed consent from research subjects (or their legally authorized representatives) Beneficence : This principle requires that researchers maximize benefits and minimize harms associated with research. Research-related risks must be reasonable in light of the expected benefits. Justice : This principle requires equitable selection and recruitment and fair treatment of research subjects . 34

35. There comes ICH In the 1980s the  European Union  began harmonising regulatory requirements. In 1989, Europe, Japan, and the United States began creating plans for harmonisation. The International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) was created in April 1990 at a meeting in  Brussels . ICH had the initial objective of coordinating the regulatory activities of the European, Japanese and United States regulatory bodies in consultation with the pharmaceutical trade associations from these regions, to discuss and agree the scientific aspects arising from product registration. [2]  Since the new millennium, ICH's attention has been directed towards extending the benefits of harmonisation beyond the founding ICH regions. This ICH GCP Guideline Integrated Addendum provides a unified standard for  the European Union, Japan, the United States, Australia, Canada, the Nordic countries and the World Health Organization (WHO). to facilitate the mutual acceptance of data from clinical trials by the regulatory authorities in these jurisdictions. 35

36. 36 The International Council(conference) for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH is an initiative that brings together regulatory authorities and pharmaceutical industry to discuss scientific and technical aspects of pharmaceutical product development and registration. The mission of the ICH is to promote public health by achieving greater harmonisation through the development of technical Guidelines and requirements for pharmaceutical product registration. ICH Guidelines  were created by The International Council for Harmonization of Technical  Requirements  for Pharmaceuticals for Human Use ( ICH ).  ICH  aims to provide uniform  standards  for technical  requirements  for pharmaceuticals for human use. They are developed by regulatory and pharma industry authorities. Harmonisation leads to a more rational use of human, animal and other resources, the elimination of unnecessary delay in the global development, and availability of new medicines while maintaining safeguards on quality, safety, efficacy, and regulatory obligations to protect public health. As per the public health ICH must include the professional qualifications in their requirements on the aspect of pharmacists must be qualified and organisations must be included only pharmacist related of all health organisation.

37. The formalization of the concept of harmonization led to immediate benefits to the regulatory authorities and the pharmaceutical industry. The ICH recommendations helped in preventing duplication of clinical trials and minimizing the use of animal testing at the same time taking care of safety and effectiveness. The recommendations also streamlined the regulatory process for new drug applications, thereby reducing the development times and optimizing resources for drug development. The ICH has since then entered the electronic era with a stress on paperless application process and sharing of real-time information among the stakeholders. The purpose of the ICH is to “make recommendations on ways to achieve greater harmonization on the interpretation and application of technical guidelines and requirements for product registration in order to reduce or obviate the need to duplicate the testing carried out during the research and development of new medicines.” From the beginning, the ICH intended to prepare harmonized guidelines/ guidances , or internationally accepted common texts for the development of new pharmaceuticals. Harmonization was viewed as a means of promoting efficient drug development by elimination of unnecessary duplication and by indicating rational drug developing procedures. The ICH brought together representatives from regulatory authorities and experts from the pharmaceutical industry and academia in Europe, Japan, and the United States. They discussed scientific and technical aspects of product registration of pharmaceuticals for human use as equal partners as well as details of the testing procedures required to ensure the assessment of safety, quality, and efficacy of medicines and regulatory obligations to protect public health. 37

38. The role of ICH-GCP is  to improve ethical awareness, trial concept and methods, public safety, cost effectiveness of research and development, competitiveness, data recognition and marketing structure . Conducting clinical trials in accordance with ICH-GCP guidelines has reduced the occurrence of frauds and accidents. Every trial is accessed for risk benefit ratio, clinical design and protocol, complete information of the investigational product, informed consent of subjects, ethical compliance and approval, qualified medical physician and clinical staff. The aim of imposing informed consents in the guidelines is to protect the integrity, rights, safety and confidentiality of trial participants. Also as per ICH-GCP, the product under study is manufactured as per GMP i.e. Good Manufacturing Practices. Clinical trial information and records are easily retrievable and accessible for accuracy, interpretation and verification of the reports. The subjects and regulatory authorities have to be informed of premature termination or suspension of any trial with an explanation. In case of any compensation, the method and manner of which should meet regulatory requirements. 38

39. To avoid any malpractices and overcome inconsistencies in clinical trial, the International Conference for Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) issued these guidelines. The Nuremberg Code, the Declaration of Helsinki, the Belmont Report, International Conference on Harmonization (ICH-GCP) Code of Federal Regulations have provided the foundation for the guidelines that have formed the basis of the ICH-GCP. Pharmaceutical companies and representatives of authorities of European Union, United States, Japan, Australia, Canada, the Nordic countries and WHO are enforced to follow these guidelines. The guidelines provide a unified standard in these regions for mutual acceptance of clinical information and data by the regulatory bodies or authorities. Good Clinical Practice (GCP) is an international, scientific, ethical and harmonised standard for conducting, monitoring, auditing, recording and reporting in clinical trials. It assures to report and record results or data of trial subjects with accuracy and protects their integrity, rights and confidentiality. ICH-GCP represents quality standards that improve data quality, minimise unwanted exposure of humans to investigational products, enhance marketing prospects of new drugs and makes trials cost-effective for sponsors. The regulatory bodies, sponsors, investigators, project monitors, patients, ethical committee or review board are required to be aware of ICH-GCP. 39

40. The ICH topics are divided into four categories and ICH topic codes are assigned according to these categories: Q : Quality Guidelines S : Safety Guidelines E : Efficacy Guidelines M : Multidisciplinary Guidelines 40

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42. In an effort to overcome international GCP inconsistencies throughout the countries, the International Conference for Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) issued the ICH Guidelines: Topic E6 Guideline for GCP. This guideline was approved on 17 July 1996 and implemented for clinical trials from 17 January 1997. The participants of these guidelines were representatives of authorities and pharmaceutical companies from the EU, Japan and the United States as well as those of Australia, Canada, the Nordic countries and WHO. This guideline was approved on 17 July 1996 and implemented for clinical trials from 17 January 1997. The participants of these guidelines were representatives of authorities and pharmaceutical companies from the EU, Japan and the United States as well as those of Australia, Canada, the Nordic countries and WHO 42