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Ibn Sina And The Clinical Trial

M. Sajadi, D. Mansouri, Mohamad-Reza M Sajadi
Published 2009 · Medicine

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Key Summary Points Although the era of formal experimentation with drugs is thought to have begun with James Lind in the 18th century, there is evidence of human trials before that. The ancient Greeks, Romans, and Persians carried out experiments with poisons and antidotes. In the 10th century, a Persian physician by the name of Razi described the first-known use of a control group in a human trial. Ibn Sina, an 11th-century Persian physician, wrote the earliest known treatise relating to clinical trials. Ibn Sina's The Canon of Medicine was a synthesis of Aristotelian, Galenic,Arabian, Persian, and Indian medicine. This was the main textbook in many European medical schools from the 14th to 16th centuries. In a chapter in The Canon of Medicine, Ibn Sina describes 7 conditions for the recognition of the strengths of the characteristics of medicines through experimentation. The therapeutic principles that are presented in his treatise are similar to concepts that define the modern clinical trial. The 7 conditions are ensuring the use of pure drugs, testing of the drug for only 1 disease, the use of control groups, the use of dose escalation, the requirement of long-term observation, the requirement of reproducible results, and the requirement of human over animal testing. Although the scientific method had yet to be formally described, Ibn Sina's treatise contained all of its components. However, the ultimate influence of his treatise on the progress of experimental design is questionable. Approximately 1000 years ago, a Persian (Iranian) physician by the name of Abu-'Ali al-Husayn ibn Abdallah ibn-Sina (commonly known as Ibn Sina, but also known as Avicenna in the West), wrote a treatise on the testing of drugs. This work, which was a chapter in his much larger The Canon of Medicine, was titled The recognition of the strengths of the characteristics of medicines through experimentation (1). The title alone is astounding, considering that the era of formal experimentation with drugs is believed to have occurred 750 years later, with James Lind's famous experiment on scurvy with lime juice (2). While the introduction and adaptation of new techniques in the design of clinical trials occurred after Lind, these developments were largely sporadic and took several centuries to advance. An important milestone was Gavarret's comprehensive work on the statistical analysis of clinical trials that was published in 1840 (3). However, clinical trials as we know them today were largely a 20th-century phenomenon; thus, it is surprising to find echoes of many modern concepts in a work from a millennium ago. Although one can envision that medical knowledge gradually advanced through the millennia via trial and error, there does not seem to be any evidence of the systematic testing of drugs before Ibn Sina's time. In an article focusing on the history of clinical trials (4), Bull notes, with regard to Greek medicine, that although the natural sequel in therapeutics would seem to be the clinical trial the Hippocratic writers with their confidence in general philosophy did not draw this conclusion. Regarding Roman medicine, he continues, Dioscorides wrote the earliest scientific account of medical botany but he did not describe the methods of testing therapeutic action. Despite this, several examples of simple toxicology experiments have been documented. In each of the following examples, different drugs were given before or after administration of the poison and mortality was the measured outcome or end point, but other crucial details about these experiments remain unknown. Mithridates VI (13263 bce), a Persian king who ruled over Pontus (present-day Turkey), tested various poisons and their antidotes on convicts (57). Pliny the Elder states that after Mithridates' death, Pompeius Lenaeus translated Mithridates' handwritten texts regarding his experiments into Latin at the request of Pompey the Great (8). However, there is scant mention of Mithridates' works by later Roman and Greek writers, with the exception of Galen (6, 7, 912). Mithridates' work appears not to have survived into modern times, and thus his experimental methods remain unknown (7). Likewise, Attalus III (170133 bce) and Galen (131201 ce) respectively tested at least 1 poison and its antidote on convicts and birds, but again, the details of these experiments are unknown (57). The description of a control group is perhaps the earliest known example of a concept associated with modern clinical trials. Approximately 1 century before Ibn Sina, a work by Razi (a Persian physician also known as Rhazes, 865925 ce) titled Hawi, described the dividing of a group of patients with meningitis into an intervention group (bloodletting) versus control (no bloodletting) to determine the efficacy of this practice (13). Although Razi's observation predates Lind by approximately 850 years and is important in its own right, the scope of what Ibn Sina would next propose was greater and more comprehensive than anything before or for many centuries thereafter. This article takes a closer look at Ibn Sina's life accomplishments and the first known treatise on clinical trials. (For the exact methods and sources used for our translation of this treatise and other parts of Ibn Sina's The Canon of Medicine, please refer to the Note at the end of the article). Ibn Sina's Biography Ibn Sina was born in 980 ce in the village of Afshona (present-day Uzbekistan) during the dying days of the Samanid dynasty (1416). The Samanid dynasty is noteworthy in that it was among the first indigenous Persian political entities to arise after the defeat and dissolution of the Persian Empire at the hands of Arab Muslims. In fact, as Ibn Sina was beginning the decades-long task of compiling The Canon of Medicine, the poet Ferdowsi was completing another classic that was decades in the making: the epic Shahnameh. It should be noted that Razi was also a product of the Samanid era. Ibn Sina was thus born into a period that was marked by the political, cultural, linguistic, and scientific reawakening of Persia (1517). Ibn Sina was still a child when his family moved to Bukhara (present-day Uzbekistan), the capital of the Samanid dynasty and one of the world's leading intellectual centers (1416). Ibn Sina's father, a Samanid governor, ensured that his son was well tutored. Ibn Sina was precocious, and according to his autobiography, he had memorized the Koran by age 10 (1416). By age 18, having studied under the famous philosopher Natili, he was well versed in Greek philosophy and Islamic theology and had become a practicing physician (1416). Although Ibn Sina would take an interest and excel in many fields, the bulk of his life's work comprised philosophy, theology, and medicine. After the fall of the Samanid dynasty in 999 ce, Ibn Sina went from city to city, fleeing persecution and seeking benefactors to support his endeavors, at times finding himself a high-ranking vizier, at other times finding himself a prisoner (1416). He started his journey in Gorgan (where he began writing The Canon of Medicine), and over the next 3 decades, he traveled through Isfahan, Rey, and other cities located in present-day Iran until his death from a recurring abdominal ailment in 1037 ce (1416). He died in Hamadan, where a mausoleum still stands in his honor. Ibn Sina the Physician The Canon of Medicine, Ibn Sina's most famous work, took over 20 years to write and was a synthesis of Aristotelian, Galenic, Arabian, Persian, and Indian medicine. In Europe, it was the main textbook (translated into Latin) in many medical schools between the 14th and 16th centuries. It was taught as late as the 19th century in some areas of Europe (1416). In the beginning of this encyclopedic work, Ibn Sina elegantly states, Medicine is a science by which we learn about the conditions of the human body. Its purpose is to preserve health when well and restore health when ill. The book is divided into 5 volumes and contains approximately 1 million words (18). The first volume is a compendium of medical principles, the second is a reference for individual drugs, the third contains organ-specific diseases, the fourth discusses systemic illnesses as well as a section of preventive health measures, and the fifth contains descriptions of compound medicines. With entire chapters devoted to exercise, preventive medicine, and travel medicine, this work was both comprehensive and prescient. Ibn Sina is credited with many varied medical observations and discoveries, such as recognizing the potential of airborne transmission of disease, providing insight into many psychiatric conditions, recommending use of forceps in deliveries complicated by fetal distress, distinguishing mediastinitis from pleurisy, distinguishing central from peripheral facial paralysis, and describing guinea worm infection and trigeminal neuralgia (1, 1924). Ibn Sina's Treatise on Drug Testing In Ibn Sina's time, the principles underlying diseases and their treatment included the humoral theory and temperaments. Although the humoral theory dates back to the Greeks, it had transformed and acquired new components through the intervening centuries and with the influence of Galenic medicine. The 4 humors, or substances, found in the body were blood, black bile, yellow bile, and phlegm, and their different states (hot, cold, moist, dry) were called temperaments (14). Each patient's specific organ and disease were considered to have a certain overall temperament based on the humors and their temperaments, and each specific treatment also had its own temperament. The physician was thus tasked with finding the right balance, and it is in this setting that Ibn Sina presented his treatise on drug testing. In the second volume of The Canon of Medicine, there is a chapter titled The recognition of the strengths of the characteristics of medicines through experimentation. In this chapter, Ibn Sina state
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