Good Clinical Practices
(Part-2)

Dr. K. H. H. V. S. S. Narasimha Murthy
Professor, Department of Kayachikitsa,
Faculty of Ayurveda, IMS, BHU, Varanasi

based on the lecture available at-“Good Clinical Practice ”

The Jewish Chronic Disease Hospital study

There is another study, the Jewish Chronic Disease Hospital study. In this study, the patients were not told that they would receive cancer cells. The cancer cells were introduced into the body without informing the patients involved in the research. The researchers believed that it was unnecessary to frighten the patients, by informing them. They wanted to avoid instilling fear in the patients, which is why they chose not to disclose the information. They introduced the cancer cells without any notification and proceeded with the study. This study, known as the chronic disease hospital study, was not presented to the hospital research committees at that time. Even though ethical committees and hospital research committees existed at the time, this study was not presented or informed to them, and no consent was obtained. Once the details of the study came to light, the researchers were found guilty of fraud, dissent, and unprofessional conduct. Therefore, the Jewish chronic disease hospital study goes against human rights.

Willowbrook study

There is another study called the Willowbrook study. This study was conducted to gain an understanding of the natural history of infectious hepatitis under controlled circumstances. Mentally disabled children at the Willowbrook State School in New York were used as participants in this research. It is an institution for mentally disabled and children with intellectual disabilities. The study was conducted from 1963 to 1966, spanning three years. In this study, newly admitted children were deliberately infected with the hepatitis virus. If parents were not willing to allow their children to be infected with the hepatitis virus, the children were denied admission to Willowbrook. The parents found themselves unable to admit their children to Willowbrook unless they agreed to their child’s participation in these studies. This is another violation of human rights.

The controversial study raised important questions about the adequacy of freedom of consent and the inadequate disclosure of the child’s risk of later developing chronic liver disease. Nothing was informed to the patients or their parents. They were not given any information about what would happen. This is yet another violation of human rights.

Milgram’s study

Like that, we have another study called Milgram’s study. Here, the school teachers were instructed to give electric shocks. They were told that it was a new teaching and learning technique, and that the shocks were given to correct incorrect responses during a verbal test. If the students gave a wrong answer, they would receive a shock. This is a violation of human rights. The Milgram study is another example of such violation.

Thalidomide tragedy

Then there is the thalidomide tragedy. Anyone who has studied pharmacology and its basics will be familiar with the side effects associated with the thalidomide tragedy. Thalidomide was a drug used in the late 50s and early 60s to treat nausea, specifically morning sickness, in pregnant women. However, it became apparent in the 1960s that thalidomide treatment resulted in severe birth defects in thousands of children. After delivery, it was found that these children had different birth defects. Within a few years of thalidomide’s widespread use in Europe, Australia, and Japan, approximately 10,000 children were born with phocomelia, leading to the ban of thalidomide in most countries in 1961. This is known as the thalidomide tragedy.

Thalidomide tragedy- a turning point

The thalidomide tragedy marked a turning point in toxicity testing. Previously, no studies or research were conducted on drug toxicity. However, after the thalidomide tragedy, people began to discuss and emphasize the importance of toxicity studies. This prompted the involvement of United States and international regulatory agencies in developing systematic toxic testing models and protocols. The thalidomide tragedy brought into sharp focus the significance of rigorous and relevant testing of pharmaceuticals before they are introduced for human use in the market. It emphasized the need for proper checking of drugs before they enter the market, and that was a turning point resulting from the thalidomide tragedy.

Development of Codes and Guidelines for good clinical practices

Subsequently, various codes and guidelines were developed based on these studies. The codes and guidelines were developed for good clinical practices. If we recall the total history, the codes started with the Nuremberg Code in 1947. Then, in 1964, we discussed the Helsinki Declaration, which was the World Medical Association’s declaration. In 1979, the Belmont Report was published, which was influenced by the Tuskegee study. In 1993, the Council for International Organizations of Medical Sciences issued its guidelines. In 1996, the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use established the guideline on good clinical practices. These developments occurred one by one based on the studies and events that unfolded throughout history.

World Medical Association

The World Medical Association is a major association that was formed to advocate for human rights and promote good clinical practices. It is an international organization of physicians established in 1947. The first assembly was held on September 17th in Paris, France. The mission of this association is to serve humanity by striving to achieve the highest international standards in medical education, medical science, ethics, and healthcare for all people worldwide. This is their motto and mission.

Prior to 1947, there was no universally accepted code of conduct governing the ethical aspects of human research, especially in modern medicine. The Nuremberg Code of 1947 emerged from the United States Council for War Crimes, which presented six points defending ethical research on April 17th. The verdict on August 19th expanded and revised these six points, adding four more, and they were titled “Permissible Medical Experiments” or “How to Conduct a Medical Experiment.” These revised ten points became known as the Nuremberg Code. The reference for further reading on this topic is provided on the slides displayed in video.

Nuremberg Code 1947–

1. Voluntary and informed consent: The Nuremberg Code of 1947 emphasizes the importance of voluntary and informed consent before starting any new clinical trial or introducing a new clinical intervention.
2. Anticipating scientific benefits: What are these benefits that need to be anticipated? We need to explain them clearly.
3. Animal experimentation first: Animal experimentation should be conducted first to examine how animals react, conduct toxicological studies, observe their behaviour, and gather relevant information.
4. Avoid physical and mental suffering: The code emphasizes the need to prevent physical and mental suffering in human patients.
5. Benefits outweigh the risk: What are the risks associated with this particular drug, and what are the benefits? If the risks outweigh the benefits, the study should not proceed. This is a crucial point.
6. No intentional death or disability: Intentionally causing death or disability with a drug is prohibited. If such effects are observed in animal experiments, the drug should not be administered.
7. Protection from harm: Patients should be protected from any harm that may arise from the study.
8. Subject free to withdraw: If a subject, who has given consent and participated in the study, decides to withdraw due to personal reasons, they are free to do so. If a study has already started, the subject can be withdrawn without any issue. This is an essential point.
9. Qualified investigators: Those overseeing the clinical study or experiment should be fully qualified individuals with the necessary expertise.
10. The investigator will stop if harm occurs: If a patient is unaware that something wrong is happening to them, the qualified individual overseeing the study will stop the study if any harm occurs. This is another important point. These ten points are part of the Nuremberg Code of 1947, which was declared to establish ethical guidelines for conducting research

The declaration of Helsinki 1964–

It is an international standard for the conduct of clinical research adopted by the International Conference on Harmonization (ICH) and Good Clinical Practice Standards (GCP). Here, the global ethical standard for medical research was approved at the World Medical Association General Assembly by a majority vote of 75 percent. Here also, 100 percent votes were not available, but the majority (75 percent) accepted this declaration. It is the mission of clinical research professionals to safeguard the health of the people. So, the major motto of Ayurveda is also “Chikitsa,” which is meant for creating Arogya for the person. It should not create any harm to the patient, which is what Ayurveda and modern medicine emphasized during the time in 1964. When it comes to the Declaration of Helsinki in 1964, they adopted the previous 1947 code, the Nuremberg Code, by the World Medical Association. The first adoption was in Helsinki, Finland, in 1964.

Belmont report

It is also considered in good clinical practices. The Belmont Report is a report created by the National Commission for the Protection of Human Subjects of Biomedical and Behavioural Research. Its full title is “Belmont Report: Ethical Principles and Guidelines for the Protection of Human Subjects of Research, Report of the National Commission for the Protection of Human Subjects of Biomedical and Behavioural Research.” The report was issued on September 30th, 1978, and published in the Federal Register on April 18th, 1979. It was named after the Belmont Conference Center, where it was conducted. The center was once a part of the Smithsonian Institution and is located in Elkridge, Maryland.

The Belmont Report summarizes ethical principles and guidelines for research involving human subjects. Three core principles are identified: respect for persons, beneficence, and justice. In clinical research, it is important to respect the person, which refers to the patient or subject who has given consent. Beneficence and justice also play vital roles. The report also highlights three primary areas of application: informed consent, assessment of risks and benefits, and selection of subjects. These principles and areas form the foundation of the Belmont Report.

The World Medical Association’s Declaration of Helsinki addresses the ethical principles of medical research involving human subjects. It has been adopted in various conferences and meetings since 1964, including in 1975, 1983, 1989, 2002, 2004, and 2008. The Council for International Organizations of Medical Sciences (CIOMS) was established in 1993 and updated in 2002, has produced detailed guidelines following the Helsinki Declaration on the implementation of the principles outlined in the Declaration of Helsinki. The guidelines, known as the “Guideline on Good Clinical Practice E6 GCP,” were originally published in 1996. The ethical pillars of clinical research encompass autonomy, beneficence, non-maleficence, fidelity, confidentiality, and justice. These principles form the foundation of ethical clinical research

Autonomy

Autonomy should involve obtaining consent from the volunteers or informed patients participating in the research project. Freely given informed consent, preferably in writing, should be obtained. Nowadays, in line with good clinical practices, recent research projects are required to be registered on the CTRI website. On this website, not only consent but also follow-ups need to be video recorded and presented when necessary. Therefore, in addition to written consent, audio and video consent have become important in current times.

Beneficence

The human subject should take precedence over the interests of science and security. It is crucial to prioritize the well-being of the human being rather than the interests of science or society. One should not consider the human being solely as a subject; their welfare should be of utmost importance.

Non-Malfeasance

Then there should not be any malfeasance, which should be preceded by a careful assessment of the predictable risks and burdens. It is crucial to thoroughly understand the burdens and risks involved. It is important to avoid any act or treatment plan that would harm the patient. One should not attempt to create or produce harm; avoidance of harm is of utmost importance.

Fidelity, duty of care-

Medical research involving human subjects must be based on generally accepted scientific principles, thorough knowledge of the scientific literature, and adequate laboratory facilities. If animal experimentation, literature study, and other relevant factors do not support a clinical study, it should not be conducted. Furthermore, such studies should only be carried out by clinically competent medical professionals; it is not something that everyone can do. Therefore, authorized and competent clinical practitioners should be the ones conducting such research.

Truthfulness -honesty

It is very important that both authors, investigators and others involved are obliged to preserve the accuracy of the results. Unfortunately, this is not always the case. When considering decimal numbers, 0.5 should be rounded to the nearest integer, either the next or previous integer. For example, 2.5 may be rounded to 2 or 3, but it should not be rounded to 2.5, Negative as well as positive results should be published in clinical research. Often, negative results are not published, keeping the public in the dark and only sharing positive results. However, it is crucial to publish both types of results. Sometimes, drugs are withdrawn when negative results emerge, even in modern times.

Confidentiality-

The confidentiality is also very important. Every precaution should be taken to the respect of the privacy of the subject and the confidentiality of the patient’s information is also important. One should not tell, one should not tell the name of the patient, story of the patient to anybody, everybody because this is very confidentially to be maintained. The confidentiality is very important in good clinical practices.

Justice–

The ethical principle states that patients entering a study should be assured of access to the best proven prophylactic, diagnostic, and therapeutic methods identified by the study. This is another important point. Research investigators should be aware of the legal, ethical, and regulatory components and requirements for conducting research. Therefore, before initiating any clinical research, it is essential to understand the legal consequences and how to avoid them, as well as adhere to ethical rules and regulatory authority regulations. Without considering these aspects, justice cannot be served. The physician should halt any investigation if the risks outweigh the potential benefits. For instance, if an x-ray procedure poses a potential risk of malignancy or other adverse effects to a patient, it should not be introduced. The investigation should be stopped in such cases.