History of Clinical Research PDF

History of Clinical Research Definition of Clinical Research Patient-Oriented Research Research conducted with human subjects (or on material of human origin such as tissues, specimens and cognitive phenomena) for which an investigator (or colleague) direc...

History of Clinical Research Definition of Clinical Research Patient-Oriented Research Research conducted with human subjects (or on material of human origin such as tissues, specimens and cognitive phenomena) for which an investigator (or colleague) directly interacts with human subjects…includes: - Development of new technologies - Mechanisms of human disease - Therapeutic interventions - Clinical Trials Epidemiologic and Behavioral Studies Outcomes Research and Health Services Research *From NIH Director’s Panel on Clinical Research, 1996 Sir Isaac Newton (1642-1727) Born in Lincolnshire, England “If I have seen a little further, it is by standing on the shoulders of giants” - Sir Isaac Newton, 1676 4  Imhotep in Ancient Egypt c. 2850 B.C. Imhotep was a known scribe, chief lector, priest, architect, astronomer and magician (medicine and magic were used together) Diagnosed and treated over 200 diseases, performed surgery and practiced some dentistry Extracted medicine from plants and knew the position and function of the vital organs and circulation of the blood system Ancient Chinese Medicine 2737 B.C. Emperor Shen Nung experimented with poisons and classified medical plants. He is reputed to have eaten 365 medicinal plants over the course of his life, turned green and died. Shen Nung (c. 2800 B.C.) Malaria, an Ancient Disease China: symptoms described in ancient medical writings 2700 BC, several characteristic symptoms of malaria described in the Nei Ching Qinghao plant (Artemisia annua): was described in the medical treatise, 52 Remedies, found in the Mawangdui Tomb In 340 AD, the antifever properties of Qinghao first described by Ge Hong of the East Yin Dynasty Active ingredient of Qinghao, known as artemisinin, isolated by Chinese scientist, Professor Tu Youyou in 1971 (Nobel Prize 2015) 5  Sushruta: Father of Indian Surgery Resided at the court of the Gupta kings ~600 B.C. (unclear) Wrote medical texts about surgery most famous: Sushruta Samhita, an encyclopedia of medical learning Counted 300 bones in human body Advocated sterilization of wounds Discussed options for instruments; hand: best instrument History of Clinical Trials “Then Daniel said to the steward… Test your servants for ten days; let us be given vegetables to eat and water to drink. Then let our appearance and the appearance of the youths who eat the king’s rich food be observed by you, and according to what you see, deal with your servants. So he harkened to them in this matter; and tested them for ten days. At the end of ten days it was seen that they were better in appearance and fatter in flesh than all the youths who ate the king’s rich food. So the steward took away their rich food and the wine they were to drink, and gave them vegetables.” Daniel 1:11 – 16 c. 530 BC Insight from the Bedside Hippocrates Greek physician born about 460 B.C.; died about 370 B.C. Hippocratic method - Observation paramount: “A great part of the Art is to be able to observe.” - Description of pulmonary edema: “Water accumulates; the patient has fever and cough; the respiration is fast; the feet become edematous; the nails appear curved and the patient suffers as if he has pus inside, only less severe and more protracted. One can recognize that it is not pus but water…If you put your ear against the chest you can hear it seethe inside like sour wine.” 6  Hippocrates’ Accomplishments Dissociated medicine from theology and philosophy Established science of medicine Provided physicians the highest moral inspiration they have Wound Management “…if water was used for irrigation, it had to be very pure or boiled, and the hands and nails of the operator were to be cleansed.” Hippocrates, 460 B.C. – 370 B.C. Iranian Medicine: Al Rhazi and Ibn Sina Al Rhazi (865-925): Discovered use of alcohol and mercurial compounds as antiseptics Contributions to medicine, alchemy, and philosophy 1st treatise on pediatrics recorded in over 184 books and articles Ibn Sina - Avicenna (973-1037): Leader in pharmacy, philosophy, medicine and pharmacology Wrote the Canon of Medicine, main European medical textbook of 14th – 16th c. Text contains 1st known treatise on clinical trials – provided foundation for systematic approach to drug testing 7  Ibn Sina (Avicenna) “The Canon of Medicine” 7 conditions for experimentation 1. Drug must be pure 2. Drug must be tested for only 1 condition 3. Drugs must be tested in contradictory disease states 4. Strength of drug must be proportionate to severity of diseases 5. Time of therapeutic effect must be considered 6. Drug must be observed for continued action 7. Drug must be tested in humans before judgment Leonardo daVinci (1453-1519) Born near the town of Vinci in Florence, Italy 8  History of the Microscope 1st C AD: Glass tested by Romans who recognized when thick in middle and thin on edges yielded magnification Ibn al‐Haythan (Alhazen ~1000): Father of Optics (Egypt) 13th C: Eye glasses invented; first eyeglasses made in Germany ~1286 1590: Zaccharia Janssen and son, Han invented compound microscope with 2 lenses in a cylinder (Dutch, Middleburg) 1609: Galileo added focusing device (Italy) Antonj Van Leeuwenhoek (1632-1723) 1660: worked in dry good store counting threads in woven cloth Made small lenses with greater curvature resulting in 270X magnification Described bacteria, yeast, sperm, striated muscle, crystalline lens, RBCs Hematology William Harvey (1578 - 1657) Defined the circulatory system 9  Hematology William Harvey (1578 - 1657) Defined the circulatory system Sir Christopher Wren (1632 - 1723) Invented IV needle. First intravenous injections (in dogs) Hematology-First Transfusions in Man Jean-Baptiste Denys (1667) June 15, 1667 – Transfused about twelve ounces of sheep blood into a 15-year old boy – who survived Richard Lower (1667) November 1667 – Transfused sheep's blood into man Hematology James Blundell (1828) First modern (man-to-man; man-to woman) transfusion Karl Landsteiner (1900) A,B, and O and AB blood types 10  History of Clinical Trials James Lind Scurvy was a major health problem for the British Navy in the 1700’s. William Harvey had recommended lemons to treat scurvy, but had argued that the therapeutic effect was a result of the acid in the fruit. James Lind, a naval surgeon, conducted a clinical trial in 1747 to assess the utility of three therapies for scurvy. (1716 – 1794) Born in Edinburgh, Scotland History of Clinical Trials James Lind - Experimental Design 12 sailors with classical scurvy, divided into six groups of two each; all given identical diets, the various groups supplemented with: - vinegar - diluted sulfuric acid - cider - sea water - nutmeg, garlic, and horseradish mixture - two oranges and one lemon, daily History of Clinical Trials James Lind - Experimental Design (cont’d) Treatment Arm Cured P Value* Sulfuric Acid 0/2 NS Vinegar 0/2 NS Sea Water 0/2 NS Cider 0/2 NS Physician’s Remedy 0/2 NS Citrus Fruit 2/2 NS!!!! *Compared to patients in the the other 5 arms of the trial; no placebo group 11  Story of Smallpox Girl with Smallpox (1) Al-Rhazi– 1st description of smallpox ~900 A.D. (2) In the 11th century, protective measures for smallpox included: Putting scabs from smallpox pustules in the nostrils Wearing the clothing of someone who had the disease Ingesting powdered fleas from infected cows (may have perceived relationship of cowpox Chinese artist rendition of a girl with smallpox to smallpox) Smallpox in 1700’s By 1720’s: Variolation practiced in Africa, China, India 1721: Lady Mary Worley Montague, wife of the British Ambassador, observed inoculation in Constantinople and introduced practice in London (inoculated her 2 children) 1745: London Smallpox Inoculation Hospital founded 12  Benjamin Jesty 1736 ‐ 1816 Jesty was a farmer who lived in village of Yetminster in North Dorset, UK. Convinced milkmaids who contracted cowpox were protected from small pox, in 1774 he inoculated himself, wife and 2 sons with cowpox lymph from underside of cow udder. In 1805 publically inoculated son Robert with live small pox to demonstrate he was still protected. Edward Jenner (1749-1823) May 14, 1776 Born in Gloucestershire, England Illustration of Edward Jenner vaccinating James Phipps Artist unknown. Undated illustration Small Pox in American History Biological warfare: used by Lord Jeffrey Amherst in 1763 during Pontiac’s Rebellion, a conflict between British and Native Americans following the French and Indian War George Washington and the Continental Army 1775 quarantine use of immune troops July 3, 1776: variolation approved by Continental Congress 13  Eradication of Small Pox D.A. Henderson, MD, MPH 1966: head of WHO’s global smallpox Last case of smallpox in eradication campaign Somalia 1974: In India during one of the largest in 1977, not until 1980 epidemics of 20th C he initiated global that WHO confident immunization program smallpox completely eradicated Genetics Mendel, the Father of Genetics Experiments in Plant Hybridization lead to a new theory of inheritance Inheritance is a “particulate” process Genetic factors come in pairs Genes are on chromosomes and Gregor Johann Mendel passed on from parents to (1822–1884) offspring during sexual reproduction 14  Barbara McClintock, PhD 1902 – 1992 American scientist and one of the world's most distinguished cytogeneticists Groundbreaking research in developing the technique for visualizing maize chromosomes Used microscopic analysis to demonstrate many fundamental genetic ideas Discovered transposition and used it to demonstrate that genes are responsible for turning physical characteristics on and off 1983: Nobel Prize in Physiology or Medicine "for her discovery of mobile genetic elements” Charles Darwin and Evolutionary Theory Charles Darwin (1859) “On the Origin of Species” In his Theory of Evolution by Natural Selection, Darwin provides a mechanistic explanation of adaptation based on natural laws, not supernatural or religious actions. “Nothing in Biology makes sense without Evolution” Created first tissue bank and demonstrated importance of Charles Robert Darwin meticulous records. (1809 –1882) Epidemiology 15  John Snow (1813-1858) Born in York, England British physician, anesthesiologist Medical hygiene pioneer Father of modern epidemiology for work in tracing the source of a cholera outbreak in Soho, England (1854) Spot map illustrates cases of cholera centered around pump Statistics illustrate connection between quality of water source and cholera cases Study was major event in public health history Washing Hands ~600B.C., Sushruta advocated sterilization of wounds ~400 B.C., Hippocrates promoted clean hands for wound management 16  Ignaz P. Semmelweis (1818-1865) Born in Budapest, Hungary History of Clinical Trials Semmelweis, 1848 - 1863 Semmelweis studied puerperal sepsis in Vienna over the protestations of his chief; he noted that the sepsis rate was three times higher in Division 1 than in Division 2; Divisions identical except medical students worked in Division 1, Midwives in Division 2. Death of a friend following infection of an autopsy- related wound led to his primary hypothesis that the infection was transported from the autopsy room to uninfected patients by the students. History of Clinical Trials Semmelweis ‐ Experimental Design Students to wash hands in chlorinated lime solution. Mortality rate dropped from 18.3% to 1.3% per year; in some months in 1848 the mortality rate was 0%. 17  Puerperal Fever Monthly Mortality Rates 35 30 25 20 15 10 5 0 Oct Oct Apr Apr Jan July Nov Jan July Nov Jan July Nov Jan July Nov Jan July Nov Jan July Nov Dec Feb June Aug Dec Feb June Aug Dec Feb Sept Sept Sept Sept Sept Sept Mar Mar Mar Mar Mar Mar May May May May May May 1841 1842 1843 1844 1845 1846 1847 1848 History of Clinical Trials Semmelweis, 1848 ‐ 1863 (continued) His chief did not believe his data; one year later he was fired. He moved to his original home in Budapest, Hungary where he repeated his earlier experiment with the same results. His major paper, “The etiology, understanding, and prevention of puerperal sepsis” was rejected by the Vienna Medical Journal and he ultimately had to pay to get his work published. Story of Antisepsis Lister’s careful trials with antiseptics were the Joseph Lister beginning of the end of post-op sepsis. The (1827-1912) carbolic sprays he advocated (shown in this 1882 Born in Essex, England engraving) were initially messy and unpleasant. 18  Surgery John Hunter (1728 – 1793) The Man who Changed the Nature of Surgery Scottish anatomist and surgeon Purchased services of grave robbers To determine the nature of venereal disease, inoculated himself with infected material from a sufferer (gave him syphilis which over the years severely damaged his heart) Anesthesia William T. G. Morton 1819-1868, dentist Demonstrated use of “letheon” (ether) Oct 16, 1846 at Mass General Hospital 19  Birth of the Pharmaceutical Industry Claude Bernard (1813-1878) Born in the village of Saint-Julien, France Pancreas in digestion Glycogenic function of liver Vaso-motor system (vaso-dilator and vasoconstrictor nerves) Curare Rudolph Virchow (1821-1902) Born in Świdwin, Poland Leukemia Omnis cellula e cellula” every cell originates from another cell (1858) Pulmonary emboli (thromobosis and embolism) 20  Louis Pasteur (1822-1895) Born in Dole, France Germ basis of fermentation, germ theory of infectious diseases Discovered staphylococci as cause of boils Described Streptococcus pyogenes as cause of puerperal sepsis Vaccine for anthrax Vaccine for rabies Introduced Petri dish, use of blood agar pour plates to culture bacteria First to describe anthrax infection (1872) Cultured M. tuberculosis and developed TB skin test Described water-borne epidemics Koch’s postulates In 1905 he was awarded the Nobel Prize for Physiology or Medicine "for his investigations and discoveries in relation to Robert Koch tuberculosis" (1843-1910) Anthrax bacillus from a Born in Hanover, Germany paper published by Koch in 1877 Emil von Behring (1854-1917) Born in Deutsch-Eylau, Germany Discovered antibodies (diptheria antitoxin) First use of passive immunization In 1901 he was awarded the Nobel Prize for Physiology or Medicine "for his work on serum therapy, especially its application against diphtheria…" 21  Paul Ehrlich (1854-1915) Born in Strehlen, Poland Described eosinophils Described complement pathway and humoral immunity Treatment of syphilis First Antibiotic for Syphilis Paul Ehrlich and Sahachiro Hata New York Times (2/9/1912) Salvarsan (Hoechst), an arsenobenzene was 32% arsenic and toxic Later, Neosalvarsan (compound ‘914’) was less toxic Ehrlich coined term “magic bullet” “We must search for magic bullets. We must strike the parasites, and the parasites only, if possible, and to do this, we must learn to aim with chemical substances!” Sir Alexander Fleming (1881‐1955) Born in Lochfield, Scotland In 1928 while working on influenza virus, observed mold on a staph culture plate with a bacteria‐free circle around itself. Penicillin discovery spawned expansion of pharmaceutical industry Awarded the Nobel Prize in Physiology or Medicine 1945 22  The Insulin Story May –August 1921: Material extracted from the islets of Langerhans (called "insulin," from Latin for "island") given to diabetic dogs; result: abnormally high blood sugars were lowered. Within 6 weeks, product purified and given to 14-year-old boy dying of diabetes. Frederick G. Banting Charles H. Best 1891-1941 1899 - 1978 Injection lowered blood sugar and cleared urine of sugars and other signs of disease. February, 1922: Banting and Best published paper on their discovery. In 1923: Nobel Prize was awarded to Banting and Macleod for the discovery, and each shared their portion of the prize money with other project researchers (including Best) 1921: U of Toronto lab of Banting and Best Under direction of C. Macleod Polio Story National Museum of Health and Medicine Jonas Salk, MD (1914 – 1995) American medical researcher and virologist Developed the first successful inactivated polio vaccine, one of the most rapid examples of bench‐to‐bedside translation in medicine In 6 year span: Key basic lab discoveries facilitating the development of the vaccine were made Optimization/safety testing completed in both animals and human volunteers largest clinical trial in history of 1.8 M children conducted, and the results released Associated incidents: Lab manufacturing errors with Cutter and Wyeth vaccine lots Questions re: statistical design 23  Albert Bruce Sabin, MD (1906 – 1993) 1954: Sabin vaccine first tested  Sabin vaccine consists of weakened forms of the viruses that cause polio 1956‐1960: Sabin worked with Russian colleagues to perfect the oral vaccine 1955‐1961: oral vaccine tested on ~100 million people in USSR, parts of Eastern Europe, Singapore, Mexico, the Netherlands Women in Clinical Research Florence Nightingale (1820 – 1910) Born in Florence, Italy Famous work in nursing Accomplished mathematician Math expertise dramatized needless deaths caused by unsanitary conditions in hospitals and need for reform Major contributions during Crimean War in promoting sanitary conditions for soldiers 24  Marie Curie (1867 – 1934) Born in Warsaw, Poland Accomplishments: ‐ Discovery of radium ‐ Realization that radioactivity is an intrinsic atomic property of matter ‐ Pioneered a mobile x‐ray unit for the French army in WWI ‐ Founded a radiological school for nurses ‐ With her husband, she was awarded half of the Nobel Prize for Physics in 1903, for their study into the spontaneous radiation discovered by Becquerel (awarded the other half of the Prize) ‐ In 1911 she received a second Nobel Prize in Chemistry, in recognition of her work in radioactivity. ‐ Daughter, Irene Joliot‐Curie, was awarded the Nobel Prize for chemistry in 1935 jointly with her husband for their discovery of artificial radioactivity Rosalyn Sussman Yalow, PhD (1921 – 2011) American medical physicist Collaborated with Solomon Berson, MD to develop radioimmunoassay (RIA) Co‐winner of the 1977 Nobel Prize in Physiology or Medicine with Roger Guillemin and Andrew Schally for development of the radioimmunoassay technique 1st female and 1st nuclear physicist to win the Albert Lasker Award for Basic Medical Research for the discovery and development of the technique of radioimmunoassay Janet Davison Rowley, MD (1925 – 2013) American human geneticist 1970’s: 1st scientist to identify a chromosomal translocation as the cause of leukemia and other cancers: abnormal Philadelphia chromosome implicated in certain leukemias was involved in a translocation with chromosome 9 in some cases Awards included: (1) National Medal of Science (2) Presidential Medal of Freedom (3) Lasker Award in Clinical Medical Research with Alfred Knudson, Jr., Peter Nowell: “for incisive studies in patient‐oriented research that paved the way for identifying genetic alterations that cause cancer in humans and that allow for cancer diagnosis in patients at the molecular level” 25  Blind Studies and Placebo Effect Benjamin Franklin In 1784: King Louis XVI of France appointed Franklin to a Royal Commission Purpose: judge legitimacy of animal magnetism as a medical cure Single-blind, placebo-controlled trial used by Commission Placebo effect noted Borrowed Ideas: Blinding  Torald Sollmann suggested a placebo control and blinded observer as a solution to investigator bias as early as 1930  Blindfold Tests: widely used by advertisers and consumer groups in the Testing gelatins at Consumers Union, 1945 1930s and 1940s 26 Statistics – Randomization Borrowed Ideas: Randomization Sir Ronald Aylmer Fisher Rothamsted Agricultural Station (1890-1962) Introduced application of statistics to experimental design Farming and plant fertility: concept of randomization and analysis of variance Medical Research Council trial led by Sir Austin Bradford Hill 1948 First clinical trial with a properly randomized control group 27  Medical Research Ethics Gerhard Armauer Hansen (1841‐1912) Born in Bergen Norway Norwegian physician 1874: Identified bacterium Mycobacterium leprae as the causative agent of leprosy Claim not well‐received 1880: inoculated live leprosy bacilli into nurses and patients without consent Court took legal action to remove Hansen from research position; retained chief medical officer for leprosy status History of Informed Consent 1898: William Osler 1849-1919 “To deliberately inject a poison of known high degree of virulency into a human being, unless you obtain a man’s sanction…is criminal.” (In response to an oral presentation by Giuseppe Sanarelli on discovery of the etiologic agent of yellow fever) 28  Informed Consent Minutes of Medical Board MEDICAL BOARD Tuesday, June 9, 1953, 3:00 p.m. Chairman: Dr. Luther Terry “…how to provide each patient with a reasonable understanding of his role in a study project and the means for obtaining evidence of such understanding and consent.” 1962: Kefauver-Harris amendment to Food and Drug Act stipulating subjects must be told whether a drug is being used for investigational purposes Surgeon General requires peer review (IRBs) for all PHS grants. 1967: FDA required all new drug sponsors obtain informed consent for use of investigational drugs in humans. History of Clinical Research - A Merging of Diverse Cultures - 29