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Clinical trials are crucial in advancing human health and the practice of medicine. From early drug discovery to late stage clinical studies and post approval, the clinical trial process continues to evolve. This evolution of clinical trials offers insight into current regulations, trial designs and practices in clinical research.
The first historically recognized clinical trial was conducted in 1747 by the Scottish physician and pioneer of naval hygiene, James Lind, FRSE FRCPE. Many scientists consider him to be the true father of the clinical trial. After many weeks at sea, the crew of the British naval ship HMS Salisbury contracted scurvy. Lind’s “observational study” convincingly confirmed that a diet including vitamin C could prevent the debilitating disease. It was not until the 1800s that another cornerstone of the development of clinical trials, the placebo, emerged. Included in Hooper’s Medical Dictionary of 1811, the term “placebo” was considered “an epithet given to any medicine more to please than benefit the patient.” 
Austin Flint, MD, one of the founders of Buffalo Medical College, the precursor to the State University of New York at Buffalo, NY, and an early president of the American Medical Association (AMA), was the first physician to conduct a medical experiment comparing a placebo to an active treatment. In 1863, he wanted to know whether drugs given for articular rheumatism changed the natural history of disease. He gave 13 patients a placebo which consisted, in nearly all the cases, of a highly diluted tincture of quassia, which, today, is used for treating anorexia, indigestion, constipation, and fever. Flint concluded that in more than 90% of patients treated with placebo, there were no significant differences in the results when he compared the placebo with the active treatment. In his book A Treatise on the Principles and Practice of Medicine, published in 1886, Flint wrote, “The favorable progress of the cases was such as to secure for the remedy generally the entire confidence of the patients.” 
Placebos, and later so-called “control groups,” allowed medical researchers to compare the validity of specific treatments. But it would take nearly another hundred years before physicians and scientists could compare mainstream and “unconventional” approaches without corrupting the medical outcomes through poor judgment, illusion, or overenthusiasm. Today, in instances where a placebo control would be unethical due to the life-threatening nature of the disease, such as in the case of cancer or hematological malignancies, an active control is used that normally includes the current (best) standard of care. This helps drug developers gather important comparator information to use in late-phase trials designed to show improvement over current therapies.
The Ethics of Clinical Trials
With a growing understanding of health and the science of medicine, medical researchers made serious efforts to refine the design and statistical aspects of clinical trials. These developments ran parallel with crucial improvements in regulatory and ethical standards. 
In an attempt to gain and improve medical knowledge, medical researchers carried out multiple clinical trials throughout the 20th century at the expense of racially marginalized and vulnerable populations—typified by the Tuskegee syphilis experiment. Recognition of these—and other—abuses led nations to articulate ethical principles for clinical research and develop regulations to ensure the protection of human subjects, as set forth in the Nuremberg Code, the Declaration of Helsinki, and the Belmont Report.
The Belmont Report, for example, identifies basic ethical principles and guidelines and outlines three fundamental ethical principles for human subject research: respect for persons, beneficence, and justice.
Today these principles are embedded as the foundation of federal research regulations, codified as 21 CFR 50 (the U.S. Food and Drug Administration [FDA] regulations on the protection of human subjects) and 45 CFR 46 (the U.S. Office for Human Research Protections’ Common Rule). These moments in history have transformed the way clinical research is conducted and have created a strong foundation to address new challenges such as complex innovative design (CID) trials, big data and the use of enabling technologies.
XClinical’s team of Clinical and technology professionals appreciate the history of clinical trials as we look toward solving the challenges of today and pursuing our vision for clinical trials of the future. Contact us to learn more about Marvin, our integrated eClinical solution that helps clinical trial sponsors and CROs harness the power of their data to better manage clinical trials.
 Collier R. “Legumes, lemons and streptomycin: A short history of the clinical trial.” CMAJ. 2009;180:23–24. | 2 Flint A, Welch WH (1886). A treatise on the principles and practice of medicine: designed for the use of practitioners and students of medicine. 6th ed., rev. and largely rewritten by the author. Philadelphia: Lea Brothers & Co. | 3 Weinfurt, K. PhD, editor-in-chief. Rethinking Clinical Trials: A Living Textbook of Pragmatic Clinical Trials. National Institute of Health (NIH) | NIH Health Care Systems Research Collaboratory. Available at: https://rethinkingclinicaltrials.org/welcome/. Last accessed October 17, 2019. | 4 National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research. The Belmont Report: Ethical Principles and Guidelines for the Protection of Human Subjects of Research. April 1979. Available at: http://www.hhs.gov/ohrp/humansubjects/guidance/belmont.html. Last accessed October 17, 2019.