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Ethics, too, are nothing but reverence for life. This is what gives me the fundamental principle of morality, namely, that good consists in maintaining, promoting, and enhancing life, and that destroying, injuring, and limiting life are evil. —Albert Schweitzer, Civilization and Ethics, 1949 Progress in medical science rests upon experimentation–-the conducting of scientific tests that utilize new and untried chemical agents, devices, and methods. Without explorations of the new and unknown, the advancement of knowledge and treatment would come to a halt. Modern biomedical experimentation involves myriad methodologies and protocols, which more or less follow a similar pathway: Conceptualization: genesis of the idea or concept; Theoretical development: mathematical, biochemical, physical, mechanical, or other conceptual development of the concept; Tangible development: transformation of the theoretical into a physical prototype; Conceptual experimentation and testing: subjecting the concept and prototype to simulated/hypothetical testing and subsequent refinement; Animal-model experimentation: utilizing animals to test the effects and efficacy of the prototype or method and subsequent refinement; and Human experimentation: utilizing human subjects to test the effects and efficacy of the refined agent, device, or method and subsequent refinement or termination of concept. It is important to note that human experimentation represents the final stage of the process, occurring only after extensive research and testing in the laboratory and on animals. Pharmaceuticals, devices, and surgical procedures, by design, have profound effects on humans, and precisely because of this, extensive ethical protocols and safeguards have been developed to protect the human subjects who undergo the experimentation and testing of new drugs, devices, and procedures. HISTORY OF HUMAN EXPERIMENTATION AND THE DEVELOPMENT OF ETHICAL GUIDELINES The development of ethical guidelines for medical experimentation conducted on humans has evolved over the centuries. In the ancient world, slaves and prisoners were utilized as subjects. Herophilus of Chalcedon (c. 320 b.c.) of Alexandria is considered the world’s first careful human anatomist. His interest in human anatomy led him to dissect corpses and also conduct vivisection on live prisoners. Among other things, he discovered the differentiation between sensory and motor nerves and made observations on the liver, retina, and ovaries. Galen of Pergamum (c. a.d. 129 to 200) conducted surgical experiments on both animals and humans, including cataract and brain surgery. He would often operate on gladiators who were wounded during combat. His anatomy and surgical works set the standard for medicine in Europe for more than 1000 years. The era of documented research experiments using human subjects began with the vaccination trials in the 1700s. Early trials often involved the inquiring physician and his own family members as test subjects. Edward Jenner (1749 to 1823) tested smallpox vaccines on his own son and other children from his neighborhood. Louis Pasteur (1822 to 1895) agonized over treating humans; he agreed to treat a human only when he was convinced that the death of his first test subject, Joseph Meister, appeared inevitable. The twentieth century saw the acceleration of medical progress, as well as an expansive development of the concept of human rights. These advances led to various codes of ethics for experimentation in the scientific disciplines. In the early 1900s, Walter Reed conducted carefully scrutinized experiments on inoculations for yellow fever. Unfortunately, the twentieth century has also witnessed medical experimentation on humans without informed consent, both under coercion and covertly. All too often the pretext of medical experimentation has been used as a justification for atrocities. Examples abound of horrific experiments conducted under the name of “medical experimentation for the betterment of mankind.” A short list includes the following: Nazi Germany during World War II. Japan’s Unit 731 in the late 1930s and 1940s. Malaria studies in the United States in 1940. Mustard gas experiments in the United States in the early 1940s. Human radiation experiments on U.S. soldiers in the 1940s and 1950s. The Tuskegee Syphilis Study in the United States, from 1932 until the 1970s. Other questionable experiments, including the Milgram psychological experiment, in which many subjects were shown that they were capable of killing other humans if ordered to do so. At the conclusion of World War II, 23 Nazi doctors and scientists were tried at Nuremberg for the murder of concentration camp inmates who were utilized as research subjects. Fifteen of the 23 were convicted. One development that came from the Nuremberg Trials was the Nuremberg Code, a list of ethical guidelines for medical researchers. Its 10 points include the following provisions: Informed consent is essential. Research should be based on prior animal experimentation. The risks should be justified by the anticipated benefits. Research must be conducted by qualified scientists. Physical and mental suffering must be avoided. Research in which disabling injury or death is expected should not be conducted. A series of ethical guidelines for medical research was developed in the latter half of the twentieth century, including the Declaration of Helsinki in 1964. It was a reinterpretation of the Nuremberg Code, with an emphasis on medical research with therapeutic intent. Two years later, in 1966, the anesthesiologist Henry Beecher wrote “Ethics and Clinical Research,” in which he described 22 examples of research studies with controversial ethics that had been conducted by respected researchers and published in major medical journals. The 1970s saw the formation of the National Commission for the Protection of Human Subjects in Biomedical and Behavioral Research (known as the “National Commission”). In 1979, the National Commission met and published the Belmont Report, which outlined three basic ethical principles that form the foundation of all human subject research: (1) respect for persons, (2) beneficence, and (3) justice. THE DECLARATION OF HELSINKI The World Medical Association developed a code of ethics for research on human subjects in 1964, which came to be called the Declaration of Helsinki. In the ensuing years, biomedical journals adopted the provisions of the Declaration of Helsinki and now uniformly require that research be performed in accordance with the Declaration. The Declaration’s introduction makes clear the need to have ethical guidelines for human subject research. It is the mission of the physician to safeguard the health of the people. His or her knowledge and conscience are dedicated to the fulfillment of this mission. The Declaration of Geneva of the World Medical Assembly binds the physician with the words: “The health of my patient will be my first consideration,” and the International Code of Medical Ethics declares that, “A physician shall act only in the patient’s interest when providing medical care which might have the effect of weakening the physical and mental condition of the patient.” The purpose of biomedical research involving human subjects must be to improve diagnostic, therapeutic, and prophylactic procedures and the understanding of the aetiology and pathogenesis of disease. In current medical practice most diagnostic, therapeutic, or prophylactic procedures involve hazards. This applies especially to biomedical research. Medical progress is based on research which ultimately must rest in part on experimentation involving human subjects. In the field of biomedical research, a fundamental distinction must be recognized between medical research, in which the aim is essentially diagnostic or therapeutic for a patient, and medical research, the essential object of which is purely scientific and without implying direct diagnostic or therapeutic value to the person subjected to the research. Special caution must be exercised in the conduct of research which may affect the environment, and the welfare of animals used for research must be respected. Because it is essential that the results of laboratory experiments be applied to human beings to further scientific knowledge and to help suffering humanity, the World Medical Association has prepared the following recommendations as a guide to every physician in biomedical research involving human subjects …. The Declaration of Helsinki is divided into three primary sections: basic principles, medical research combined with clinical care (clinical research), and nontherapeutic biomedical research involving human subjects (nonclinical biomedical research). Provisions of the Declaration provide guidance on the following topics: Study design and experimental protocols; Research conformity with institutional guidelines and local and national laws; Risk assessments and risk/benefit comparisons; Consideration and protection of test subject rights; Hazard avoidance; Informed consent of legally competent and legally incompetent test subjects; Volunteer status of research subjects; and Discontinuation of research that proves harmful to test subjects. The complete text of the Declaration of Helsinki can be found at http://www.wma.net/e/policy/b3.htm. THE DECLARATION OF HELSINKI AND PLASTIC AND RECONSTRUCTIVE SURGERY The Journal adheres to the Declaration of Helsinki and its provisions; abiding by the Declaration’s guidelines is a requirement for conducting and subsequently publishing clinical research in Plastic and Reconstructive Surgery. An important element in the submission of manuscript to the Journal is a clear statement in the Methods section that the study was approved by an author’s institutional review board and that it provided written or otherwise well-documented informed consent for all patients involved. If an author is not affiliated with an institution and has no institutional review board through which to obtain study approval, the author must abide by the Declaration of Helsinki and obtain written informed consent of study subjects. In addition, authors need to state the methods by which informed consent was obtained from the study participants (i.e., verbal or written). Please see the complete Instructions for Authors, printed in the January and July issues of the Journal and available online at www.PRSJournal.com and also on the Journal’s Enkwell, at www.editorialmanager.com/prs. Plastic and Reconstructive Surgery is proud to uphold the provisions of the Declaration of Helsinki, registering clinical trials and similar related patient-safety initiatives in the ongoing effort to improve the level of health care and patient protections. We trust that most, if not all, researchers are already well versed with the Declaration and its provisions and will continue to incorporate them in their research and reporting efforts. Medical science has proven time and again that when the resources are provided, great progress in the treatment, cure, and prevention of disease can occur. —Michael J. Fox
Rod J. Rohrich (Wed,) studied this question.