A Brief History of the Development of Clinical Research

Principals, Guidelines, and Regulations

Hippocratic Oath

The Hippocratic Oath was likely written between the 5th and 3rd centuries BCE. Its purpose is to set ethical standards for medical practitioners, emphasizing principles such as confidentiality, non-maleficence (“do no harm”), and the duty to teach medicine to the next generation. Over the centuries, the oath has been revised to fit contemporary medical ethics, yet it remains a foundational pledge for physicians worldwide, reflecting their commitment to ethical medical practice. Up until World War II, the Hippocratic Oath was the main protection for patients undergoing experimental treatments.

Nuremberg Trials and Code

The Nuremburg Trials spearheaded the generation of most of the current principles, guidelines, and regulations for clinical practice. The trials prosecuted Nazi physicians who conducted inhumane and unethical experiments on prisoners of war. The physicians argued that their experimentation did not violate any laws, as there were no existing regulations or guidelines at that time indicating the ethical implications of their research. In response to this rationale, and with the aim of safeguarding the rights of research participants, American physicians present at the trials developed a comprehensive 10-point list, known as the Nuremberg Code, outlining principles for conducting research. The defendants of the Doctors’ Trial were eventually prosecuted based on the principles of Hippocratic ethics.

The 10-point list of instructions (The Nuremberg Code), created in August 1947, provided the framework for Good Clinical Practice (GCP) guidelines. The significance of the Nuremberg Code lies in its dual purpose: to ensure that researchers prioritize the best interests of human subjects, and to empower participants with the ability to protect themselves.

Declaration of Helsinki

In 1964, the World Medical Association developed a formal statement of ethical principles, highlighting essential points from the Nuremberg Code. This statement, known as the Declaration of Helsinki, serves as guidance for all study personnel and participants in medical research involving human subjects. The statement’s introduction includes the phrase, “The health of my patient will be my first consideration”, symbolizing that research and experimentation are to be patient-centered.

Thalidomide Disaster

In the late 1950s and early 1960s, Thalidomide was marketed as a treatment for morning sickness in pregnant women without proper testing for its impact on fetal development. This oversight led to thousands of babies being born with severe deformities, such as malformed limbs and heart defects. The scandal prompted stricter regulations on drug testing and approval processes worldwide.

The Tuskegee Syphilis Study

The Tuskegee Syphilis Study, conducted between 1932 and 1972, was a profoundly unethical clinical study by the U.S. Public Health Service. It involved 600 African American men in Macon County, Alabama, of whom 399 had latent syphilis and 201 served as controls. The men were misled and not given proper treatment, even after penicillin became a widely accepted cure. The study aimed to observe the natural progression of the untreated disease. The unethical nature of this study sparked outrage and led to significant changes in U.S. law and regulation regarding the protection of human subjects in clinical trials including the creation of the Belmont Report.

The Belmont Report

The Belmont Report, published in 1979, is a cornerstone document in the field of bioethics, drafted by the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research. It outlines fundamental ethical principles and guidelines for conducting research with human subjects. The report emphasizes three core principles: respect for persons, beneficence, and justice. These principles ensure that research participants are treated with dignity, informed about the study, and protected from harm while ensuring fair distribution of the benefits and burdens of research. The Belmont Report has profoundly influenced ethical standards and regulations in research practices worldwide.

International Conference on Harmonisation

A difference in standards arose when countries such as Japan, the UK, and other European committees developed their own clinical standards. A series of conferences, known as the International Conference on Harmonisation of Good Clinical Practice (ICH-GCP), was held in the 1990s to unify these guidelines and create a standard for operating clinical studies. ICH-GCP now serves as a unified standard for the European Union (EU), Japan, and the United States to facilitate the mutual acceptance of clinical data by the regulatory authorities in these jurisdictions.

ISO 14155

ISO 14155 is an international standard that outlines the requirements for the clinical investigation of medical devices for human subjects. It ensures that the design, conduct, performance, and reporting of clinical studies are carried out ethically and scientifically. This standard emphasizes the protection of human subjects, the integrity of data, and the reliability of study results. It covers aspects of study planning, conduct, and documentation, ensuring compliance with regulatory requirements. Adhering to ISO 14155 helps manufacturers demonstrate the safety and effectiveness of their medical devices, fostering trust and facilitating market approval.

In summary, the evolution of clinical research principles, guidelines, and regulations has been shaped by historical events and ethical lapses. From the Hippocratic Oath to ICH-GCP, each milestone has contributed to safeguarding human subjects and ensuring the integrity of clinical trials. These frameworks have established a foundation for ethical and scientifically sound research, fostering trust in the medical advancements emerging from clinical studies.

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