IPPCR 2015: Welcome & History of Clinical Research: A Merging of Diverse Cultures



good evening everybody my name is John Gowen and I'm the director of the clinical Center and a co-organizer this course along with Fred agna Bonnie who is on leave won't be at the NIH today and on behalf of the entire faculty of the NIH who will participate in this course and faculty from outside the NIH welcome we hope this course proves to be an exciting opportunity for all of you and in a moment I'll tell you how many folks are taking this course in addition to the folks who are assembled here at the NIH Clinical Center so I'm gonna start off by giving you some review of the course and then I will go into the topic of the first talk on the history of clinical research so this is an exciting year this is our 20th anniversary of this course it started in 1995 in a small classroom here in this building when we had about 15 students taking the course and it's grown in actually was 25 students now we have about 4,800 or actually I was told by today's registrants over 5,000 students taking the course right now so it's a little modest growth over these 20 years and we use long distance learning techniques to reach 102 off-site centers worldwide and more than 80% of our students are off-site or close to 4,000 now give you a few more pieces of data of the off-site locations 58 or in the United States and 30 of them are new this year and internationally there are 45 sites and 24 of them our new so to all the folks off site we welcome you and you'll hear in a moment how you can interact with the faculty so the textbook for this course is titled principles and practice of clinical research which is now in the third edition and you can get this online or at the NIH FAS bookstore and there's a new location here at the NIH and building 10 first floor near the Missouri oratorio handouts for each talk will be posted on the course website which is shown on this slide and we ask you to please fill out evaluations of each lecture which will appear on the course website following the lecture we use this to give feedback to the speakers and we also use this to decide who gets to speak next year and who doesn't so we really appreciate your taking a little bit of time to give us some feedback there's also a video archive of each talk and these will be posted within 48 hours following the presentation any questions that you have related to a talk can be submitted to the course coordinator mr. Danielle McNally at the website indicated here and he will see that all questions are funneled to the person who gives the lecture and then you'll get a response at the end of the course there's an exam and the examination will be posted on the course website so you can take it as an open-book exam certificates will be granted to anyone who gets a grade of 75% or higher when taking this test so if you have any questions about the course you can call the number at the bottom three oh one four nine six nine four two five and your questions will be answered so this discussion board feature is on the web and this provides an opportunity to interact on the through the web and this is the site that you can reach I guess the website is what I showed you a few minutes ago so let me go through the outline for the course there's a series of modules the first one is called study design measurement and statistics and includes all the talks bulleted on this slide I will not read each one of them you can look into the handouts of the course outline but you can see this includes the introduction to statistical design and statistical methods which is so important in the business of clinical research the second module ethical legal monitoring and regulatory considerations addresses legal issues and clinical research ethical principles data and safety monitoring committees the institutional review boards and there's a session with a mock IRB which has always been very popular and then a talk on research with vulnerable participants the third module preparing and implementing clinical studies has a series of talks focusing on developing protocols and manuals evaluation of the budget things like scientific conduct FDA product regulation and other regulatory acquirements the fourth module is addition study additional study designs and miscellaneous topics and ranges from tech transfer to dissemination and implementation of research health disparities research and how to deal with the media so we have a wonderful student body who are taking this course literally throughout the world and we look forward to your feedback and hope that this is proves to be useful so the topic that I'm going to cover is an overview of the history of this business which is after all risky business for the patients as well as big business for the pharmaceutical industry and the biotechnology industry but we can learn a lot from going back to the beginning and seeing some of the things that happen so I will try to give you a survey it's sort of a hobby of mine and I enjoy it and I want to just say right out front at the beginning that it's impossible to cover everything and to recognize everyone and if I omitted your favorite historical feature you can tell me next time I'll try to include it but I apologize but there's literally thousands and thousands of superstars that make this a wonderful story so let me start with the definition of clinical research and this is not a historical definition but it sets a perspective for the course this was produced at NIH in 1996 in a special panel that met here and divided clinical three research into three broad categories patient oriented research epidemiologic and behavioral studies and outcomes research and health services research so patient oriented research which is the one we most frequently think about if we're doing clinical research is research conducted with human subjects or material of human origins such as tissues specimens and cognitive phenomena for which an investigator or colony directly interacts with human subjects and includes the development of new technologies mechanisms of human disease therapeutic interventions and clinical trials so these three categories patient oriented research epidemiologic and behavioral studies and outcomes research and health services research is what you're going to be thinking about during this course so I love this quote which comes from Isaac Newton who in 1676 wrote if I have seen a little further it is by standing on the shoulders of giants and that's applicable to anyone who's succeeded in doing clinical research over the many millennium it's hard to know when clinical research started but in 2850 BC Imhotep who was a known scribe a chief Lecter and a priest and architect astronomer and a magician and at those days medicine and magic were used together he diagnosed and treated over 200 diseases performed surgery and practice some dentistry and he extracted medicine from plants and knew the position and function of the vital organs and circulation in the blood system so this was 2850 BC the Chinese here we are 2737 BC according to the source that I had we're also exploring medicine Emperor Shang Nong experimented with poisons and classified medical plants he's reputed to the 365 medicinal plants over the course of his life supposedly he turned green and died now I'm going to go through some examples as I go through this talk and some of them I will go from the ancient to the present just to give you a perspective and one of them is malaria which is an ancient disease first described in China in ancient medical writings in 2700 BC several characteristic symptoms of malaria were described in the niching and a plant called king-queen howl or Artemisia annua was described in some medical treatises and 52 remedies were advocated as found in the Mwangi tomb in 340 ad the anti fever properties of this plant Qing how was first described by Jihan in the East End dynasty and the act of ingredient known as artemisinin was recently isolated by a Chinese scientist professor to you you in 1971 and I had a chance to meet dr. yu yu because she received the Lasker Award in clinical research in New York the same year that the clinical Center received the Lasker Award in public service and she said that what she did was she was asked apparently by Mao earlier to find some medicines for malaria because the Chinese army needed these in where they were going and she went to this old literature and found that this Artemisia plant was reported to be helpful and people had been working on it and extracting a looking for the important element using alcohol to take the leaves and mix them with alcohol it didn't work and she went back to the original readings and they said now that won't work you got to use water and so she extracted the leaves with water and came up with the active ingredient and with her colleagues the biochemical structure which is shown here was identified and she developed this new drug which has literally literally save millions of lives throughout the world and just this month she received the Nobel Prize for this work the first Chinese investigator to ever receive a Nobel Prize I'm also going to tell you about some of the areas of Medicine and we'll spend a few minutes on surgery she's ruta is the father of indian surgery and many would say was perhaps the father of surgery he lived about 600 BC although this is not completely clear and lived with the era of the Gupta Kings he wrote medical texts about surgery and his most famous Sushruta Samhita is literally an encyclopedia of medical learning from his day he counted the bones in the body and he came up with 300 does anybody in the audience know how many bones people think are in the human body today or no there in the human body today no respondents so I'll make it easy it's it depends on when you take the measurement at birth it's said there's about 300 bones and then the bones fuse so that in the adult is probably about 206 bones so he was remarkably accurate remember this is 600 BC he also realized the importance of keeping wounds clean he did not use the word sterilization but he talked about clean wounds any discussed options for instruments in surgery and conclude that the hand was the best instrument available so you can go to all sorts of places to get insights into clinical research and perhaps the earliest so-called trial is I'll call it comes from the Bible the Book of Daniel and Daniel said test your servants for 10 days and let us be given vegetables to eat and water to drink now us is a group of Jews who were captured by the Egyptians and they didn't want to have to eat the non kosher food and so he was clever and so to avoid that he said conductores tests so give us vegetables to eat and water to drink and compare your servants who will get rich foods so then let our appearance and the appearance of the user leads the Kings rich food be observed by you and according to what you see deal with your servants so we hearken to them on this matter and tested them for 10 days and at the end of 10 days it was seen that they the ones who ate the vegetables and water were better in appearance and fatter in flesh than all the users who ate the Kings rich foods so the steward took away their rich food and the wine and gave them vegetables so this is in the Bible there's no informed consent but perhaps the greatest mind in early medicine and clinical research was Hippocrates who was born about 460 BC and died about 370 BC and you all know about the Hippocratic method and what Hippocrates advocated was observation and he said a great part of the art is to be able to observe and he recorded a whole over a hundred descriptions of clinical situations let me read you one his description of pulmonary edema he said water cumulates the patient has fever and cough the respiration is fast the feet become indominus 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 possible water if you put your ear against the chest you can hear it seize sieve inside like sour wine so this was incredible and I've had a chance to read a bunch of these his descriptions and they're remarkable for how accurately he observed and described his patients so he had some amazing accomplishments he dissociated medicine from theology and philosophy he really established the science of medicine and of course he provided physicians the highest moral inspiration that they have wound management is something he wrote about and he said if water was used for irrigation it had to be very pure and boiled and the hands and nails of the operator were to be cleansed this was long before anybody recognized infection infectious diseases and this was from Hippocrates so you're gonna see that we're going to be going around the world and hearing about investigators or champions of clinical research from everywhere and let's focus on Iranian medicine for a moment there were two individuals al-razi and Evan Seba Sina so Rossi lived about 865 to 925 and he discovered use of alcohol and mercurial compounds as antiseptics he made numerous contributions to medicine as well as alchemy and philosophy but he actually wrote the first treatise on pediatrics and this was recorded in over a hundred eighty-four books and articles now even Sina or even Sina as he was called lived from 973 to 1037 ad and he was a leader in pharmacy philosophy medicine and pharmacology and he was the principal author of the Canon of Medicine which was the main European medical textbook it had been modified obviously over the centuries but it was active particularly from the 14th to the 16th century and this book contains the first known treatise on clinical trials and provided the foundation for systematic approach to drug testing I just want to go over with you what was said back then around 1000 AD so the seven conditions for experimentation first if you want to experiment with something it should be pure second the drug must be tested for only one condition at a time third drugs must be tested in contradictory disease states for strength of a drug must be a proportionate to the severity of the disease fifth time of therapeutic effect must be considered six drugs must be observed for continued action and seven a drug must be tested in humans before judgment so this was pretty amazing when you think of when these conditions were defined so now I'm going to be skipping a couple of centuries and start talking about anatomy and to my thinking one of the the greatest early anonymous was Leonardo da Vinci this is the only self-portrait of him that's known to be available he did this near the end of his life and if you go through his works and you look at his descriptions drawings of the human anatomy it's really quite phenomenal and here a couple of pictures the microscope was an important addition to medicine in clinical research so let me tell you in a slide a little bit about the microscope in the first century AD glass was tested by the Romans who recognize when thick in the middle and thin at the edges you got magnification in and I'll hate them who lived in Egypt was the father of optics he was also a great astronomer the 13th century eyeglasses were invented the first eyeglasses were made in Germany in 1286 in 1590 zekkariyas Janssen and his son who were Dutch invented the compound microscope with two lenses in a cylinder and in 1609 Galileo added a focusing device and that was the beginning of the microscope but it was Anthony van Leeuwenhoek who first used a microscope in clinical research he lived in the 1600s to the 1700s and he worked in a dry goods store and he needed to count the number of threads in an inch or in a certain amount of space to judge the quality of the linens that were being produced and so he made special small lenses which could magnify up to 270 power and in the bottom of the slide is his first microscope and I got a facsimile of that that I found in a small store in Maine of all places and you can see this is the lens and you can put an object on it and you look through the other side and position your object with this screw and using this he described the first bacteria yeast sperm striated muscle crystalline lens of the eye and red cells among others and you could imagine sitting there and looking at a light and then making drawings of this it's really quite phenomenal so having described red cells it makes me want to bring to your attention William Harvey who lived in England from 1578 to 1657 and he was the one who really defined the circulatory system in in great detail and accuracy in the same period a little later so Christopher Wren who you probably know for his architecture he also invented the intravenous needle it was made out of sterling silver and he connected the bleeder the the needle to the urethra and infused dogs with opiates and was the first to describe the effects of intravenous opiates in a mammal he also gave the needle to a friend of his who's shown on the bottom of this slide Richard Lauer who in 1667 did the first transfusion into man using sheeps blood and the man survived probably because he only gave about ten cc's of blood and a few months earlier John Baptiste Enys in France gave about the same 12 ounces of sheep blood into a fifteen year old boy who survived but the first use of man to man or man to women or transfusion was by James Blondell who in 1828 did a number of transfusions without any typing and cross-match jingyan about half of the 12 subjects he describes survived and he was able to show in this itching which appeared in Lancet in 1828 that he could save a person who was exsanguinated after a woman after a neuter and a operation that wasn't going well he saved her life of course the advent of blood types was not until 1900 when Karl Landsteiner who was working at the Rockefeller University to find the ABO and ami blood types and that was the beginning of really the modern transfusion medicine approaches that we have now in terms of modern terminology or thinking maybe the first clinical trial was done by James Lind and he worked in England in the 1700s and at that time scurvy was a major health problem in the British Navy and william harvey who i had mentioned earlier had recommended lemons to treat scurvy but had argued that the therapeutic effect was a result of the acid in the fruit and it was Lind who was a naval surgeon conducted a clinical trial in 1747 to assess the utility of three therapies on scurvy so he took 12 sailors sailors with classical scurvy divided into six groups of two each and all were given identical diets and the various groups were supplemented with either vinegar dilute sulfuric acid cider seawater nutmeg garlic and horseradish mixture or two our oranges in one lemon daily and here are the results of all his studies the only thing that worked was Citrix root and it was not significant but of course they didn't have statistics in those days so he wrote a paper which is shown on this slide and became famous because based on these data scurvy was prevented in the Navy by giving people citrus fruit so let me move on now to smallpox as you'll see as I go through the rest of this talk I happen to have a profound interest in infectious diseases because that's my area of clinically and in immunology so let's talk a little bit about smallpox which has a pretty neat history smallpox was first described by al-razi who I had mentioned earlier probably about 900 AD in the 11th century there actually were protective measures being used throughout the world taking scabs from smallpox pustules and putting them in the nostrils of a healthy subject and that actually offered some protection if you didn't get smallpox people were wearing the clothing of someone who had the disease people ingested powdered fleas from infected cows which may have perceived a relationship of cow pox to smallpox in the 1720s the process of what's called violation was practiced in Africa China in India where you would take a scab from a patient who had smallpox remove it from the subject and take the contents of that scab and scratch it into a healthy person most people got protected some people got smallpox and Lady Mary Worley Montague who was British and the wife of the British ambassador observed in Turkey and constant opal this violation process since she brought it to London and she even inoculated her own two children and a hospital for smallpox inoculation was founded in London in 1745 using this approach the first known use of cow pox to protect against smallpox was done by Benjamin Jesty who lived in 1736 to 1816 and he was a farmer who lived in a village of yet Minister in Northeast United Dorset in the United Kingdom and he was convinced that melk maids who contracted cow pox were protected from smallpox and in 1774 he inoculated himself his wife and two sons with cow pox lymph from the underside of a cow udder and in 1805 he publicly inoculated his son Robert with live smallpox after that he had inoculated or immunized them and he demonstrated that his son was protected so this was before Jenner but what Jenner did in 1776 was actually do a large study and here you see him vaccinating James Phillips the the first person who was vaccinated and he did it large study and he recorded the data and talked about it and it was after Jenner's work with smallpox that a vaccine that was efficacious was developed now before we conclude smallpox I just want to mention one historical fact I don't want to dwell on Lord Geoffrey a mercy actually did the first biological warfare taking blankets from people who were infected with smallpox and giving it to the Indians in the french-indian war it was pretty horrible but George Washington did something remarkably clever in 1775 and 1776 when the British were surrounding Boston and the Continental Army in the United States was threatened the British Army had an epidemic of smallpox which had not hit the Continental Army in Washington made a decision that he wanted to do their viral ation technique in the soldiers but he wouldn't do it without the consent of the Continental Congress and so he got John Adams who on July 3rd 1776 the day before the Declaration of Independence was signed he got Adams to get the Continental Congress to give approval for mass immunization of the Continental Army and this was to my knowledge the first example of a mass immunization of in the military or probably anywhere else and it worked probably saved the army and enabled the United States to be or the Continental Army to beat the British eventually and now of course smallpox has been eradicated through the work of DA Henderson and the last case was in 1977 and the World Health Organization declared smallpox completely eradicated in 1980 so genetics we all know about genetics we know about Mendel who was the father of genetics working with plants and you may not know about Barbara McClintock who lived from 1902 to 1992 and was fabulous cytogeneticist and did groundbreaking research and developing the technique of visualizing maize or corn chromosomes and used microscopic analysis to generate many fundamental ideas and discovered transposition and used it to demonstrate the genes a response for turning physical characteristics on and off and in 1983 she won the Nobel Prize for her discoveries of mobile genetic elements and you know about Darwin who lived it when 1859 published his book on the origin of the species you may not know that he created the first tissue bank and demonstrated the importance of meticulous records during his travels he took tissues from all the different species that he studied and he actually created a tissue bank so clinical medicine depends on epidemiology for much of the work and I want to just mention John Snow who was an anesthesiologist who lived from 1813 to 1858 who was British and he was a real medical hygiene pioneer and really the father of modern epidemiology for work tracing the source of a cholera epidemic in Soho England in 1854 and he created this spot map in the city of London and Soho to illustrate each case of cholera during this epidemic and he demonstrated that it all centered around a water pump and he Illustrated the connection between the quality of water source and the cholera cases and he said remove the water pump and you'll get rid of the cholera and they did and then the community went ballistic and because they had to walk long distances to get the water so they reopened it the cholera came back so he really proved his point then they closed the pump and the epidemics subsided so this was a major event in public health history maybe the greatest public health invention in the 1800s was by Semmelweis so I'll tell you about in a minute but remember what I told you that so true des had advocated sterilization of wounds and Epocrates promoted clean hands for wound management but it was this man agnes Semmelweis who really solidified the importance of sanitation in medicine and he lived from 1848 to 1863 a short life he studied purple sepsis in vienna over the protests of his chief he was an anesthesiologist he had noted that the sepsis rate was three times higher in Division one in his hospital of an individual – and these two divisions were identical except medical students worked in Division one and midwives and Division two he had a dear friend who died following infection of an autopsy that his friend did he was apologist and it was what top seen a patient who had a wound similar to purple sepsis and this led him to the primary hypothesis that the infection that was seen in the women who were delivering babies came from the autopsy room by the medical students to these women who were giving birth so he said the students had to wash their hands and he used chlorinated lime solution the space and still exists that he used and when he did that the mortality rate dropped from 18% to 1% per year and in some months in 1848 it was zero and these are the data that he published and you can see by this yellow line which is the number of women who had sepsis who who died and the red arrow is when he started having them wash their hands and it immediately plummeted so he told his chief about this and the chief didn't believe his data and he was fired so then he moved to Budapest Hungary where he repeated these experiments and got the same results and he wrote a paper the etiology understanding and prevention of purple sepsis and it was rejected by the Vienna medical journey journal and ultimately he had to pay to get this work published but it was published and I can tell you he had a sad outcome he went crazy because nobody believed him and he was admitted to a mental hospital and he cut his leg on the edge of a bed and he died of the purple sepsis his work was known by some folks in the United States and I'll tell you about that in a second but in the interim in 1882 Joseph Lister also was working on the importance of sepsis in the operating room and he used carbolic sprays to clean wounds open wounds and he showed that this would reduce infection so the person who advocated for Semmelweis was Oliver Wendell Holmes senior the father of the great Supreme Court justice in the United States who was an obstetrician who worked at Massachusetts General Hospital and he didn't repeat some Eliza's experiments but he believed them and he went around and spoke this up and and certainly we got clean hands and washing hands is an integral part of the public health of hospitals sadly it's still a huge problem and I can tell you in this hospital at the NIH Clinical Center a few years ago we had an epidemic of a multi drug-resistant Klebsiella infection and it was clearly linked to people not washing their hands in an aggressive enough fashion so thing as simple as washing hands is phenomenally important so let me tell you a little more about surgery more modern surgery I can't escape telling you about John Hunter who lives in 1728 to 1793 who really changed the nature of surgery he was a Scottish anatomist and a surgeon his older brother was an established surgeon and his mother didn't know what to do with him so she sent him to work with his brother and his brother who was a surgeon told him to go out and Rob graves and he became they would take these corpses and teach anatomy to people who were interested and he became quite the skilled anatomist and then surgeon and one of the things he did is determined the nature of venereal disease and he actually inoculate him himself with an infected material from someone who had syphilis and he got syphilis and he eventually had heart damage from the syphilis there's a great book called the nice man and if you're interested I suggest you read it it's it's a very colorful book about his life anesthesia we we can't mention without mentioning William T G Morton who was a dentist who lived from 1890 to 1868 and he demonstrated that ether which he called lethean worked and he did its demonstration at 1846 October 16 1846 at Mass General Hospital in Boston demonstrating that surgery can be conducted on a person while they were asleep with no pain so with that background now let me bring you some stories about the pharmaceutical industry and I would like to start that with mentioning Claude Bernard who was French and lived in from 1813 to 1878 and among his accomplishments he recognized the pancreas was important in digestion he described the glycogenin function of the liver he described the vasomotor system the vasodilator and vaso constrictor nerves and he discovered kirari and its application in medicine rudolf virchow who lived from 1821 to 1902 was polish he defined leukemia and he wrote hominis cellular a failure every cell originates from another cell so he defined stem cells probably the first person he also defined pulmonary emboli as related to thrombosis and embolism what am i heroes historically is Pasteur who lived from 1822 to 1895 if you look carefully at this picture you'll note that his right arm is sort of just hanging was and that was because at a young age he had a stroke and he couldn't use his right arm and despite that was able to make his phenomenal discoveries including the germ basis of fermentation germ theory of infectious diseases he discovered Staphylococcus I is the cause of boils he described streptococcus pyogenes as the cause of purple sepsis the disease Semmelweis studied he made the first vaccine for anthrax and of course the vaccine for rabies Koch who lived in a similar era from 1843 to 1910 developed the petri dish and the use of blood agar pour plates to culture bacteria he was the first to describe anthrax infection before Pasteur made the vaccine he described and cultured tuberculosis the first person to do that and he developed a TB skin test he described waterborne epidemics he made as Koch's postulates and in 1905 was awarded the Nobel Prize for his work on tuberculosis and if you look in his book and I have a copy of his book these are all hand drawings here he was drew the anthrax bacillus Berry who lived in Germany from 1854 to 1917 discovered antibodies first person to describe them for diphtheria and he was the first to use passive immunization to treat a person who had been exposed and he won the Nobel Prize in 1901 Paul Ehrlich who was Polish described eosinophils is a medical student he described the complement pathway in the humoral immunity system but he also developed the first antibiotic in this case to treat syphilis and he worked with his technician shara shara hata and they developed what Hope's called salvarsan which was in our arsenal benzene which had 32% arsenic and was toxic and later they developed a compound that was less toxic cult compound 904 and Ehrlich said we need magic bullets 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 so this was the first description of the need for antibiotics and of course Fleming who in 1928 while working on influenza virus observed mold on a staff culture plate with a bacteria free circle around it most people probably would have just thrown it out but he asked why was there no bacteria around this mold and he discovered penicillin and won the Nobel Prize in 1945 insulin is an interesting story and it gets a little bit about scientific ethics in the summer of 1928 21 material extracted from this islets of langerhans called insulin from the latin for island was given to a diabetic dogs and the result was that abnormally high blood sugar levels were lowered within six weeks Banting and best Banting was a junior scientists and best was a technician they had purified insulin and gave it to a 14 year old boy who was dying of diabetes and and they basically just saved this kid's life their boss or their paper was published in 1922 but their boss in 20 1923 shared and his name was MacLeod shared the Nobel Prize with Banting and MacLeod was away during the whole time that this study was done he was on vacation his summer vacation but it was in his lab so MacLeod won the Nobel Prize with Banting and best who was the technician didn't get anything because technicians didn't win Nobel prizes in those days the good news is that MacLeod and Banting shared all their money with the folks in the lab who did the work but the credit from the Nobel Committee went to Banting and MacLeod and it was very sad that best didn't receive the Nobel Prize which he clearly deserved polio so you've all heard of Salk and Sabin but the Nobel Prize went to Enders Weller and Robbins who developed the technique for culturing the polio virus which eventually led to the vaccine and the Salk vaccine was the first and used an inactivated polio virus that was given subjects and there was a serious bad incident with the development of this vaccine there was a lab manufacturing error by Qatar when they were in activating the virus they extrapolated rather than getting data to the critical dose needed minimal dose can activate the virus and actually gave polio I think to the first thousand or so people who receive the vaccine but then that was fixed and then the vaccine was developed but Saban's vaccine is probably a better vaccine because it's a live virus vaccine and you get immunity if you one child in a classroom gets this vaccine the whole classroom will get it so it's it's sort of a perfect vaccine and Sabin worked with Russian colleagues to prevent this vaccine in the late 1950s and and you know that it worked marvelously I haven't mentioned to mention too much about women because there weren't many women who were doing science in the old days but let me mention a few superstars who lived from the 1800's on Florence Nightingale is the first she was a great mathematician and her parents really told her not to go into math because they didn't think it was the ladylike thing to do and so they told her she had to go into nursing but she was this mathematician and she used this skill in the Crimean War she showed that overcrowded hospitals she worked out the mathematics for how crowding would lead to transmission of infection and she said you had a good ventilation and spread the beds apart and doing that she reduced the intra Hospital infection rate dramatically Marie Curie is has an amazing story she discovered radium she realized that radioactivity is an at-risk trinsic atomic property of matter you may not know she pioneered a mobile x-ray unit for the French army in World War one and founded a radiologic school for nurses with her husband she was awarded half the Nobel Prize in Physics in 1903 for their study into the spontaneous radiation discovered by Becker Elle who was awarded the other half of the prize then she went it when a second Nobel Prize in 1911 her husband had died for her work in radioactivity and her daughter Irene joliot-curie 8 was also awarded a Nobel Prize for work with her husband on the discovery of artificial radioactivity so this is the first example of a parent/child Nobel laureates whatever that's worth and then Rosalind yellow who was a medical physicist collaborated will Solomon bier sin' and invented the radio immune assay and person died so he didn't win the Nobel Prize but Rosalyn Yalow did in 1977 she was the first female and first nuclear physicist to win the flask award as well and Janet Rowley who died just a few years ago was an American geneticist in the 1970s she was the first scientist to identify chromosomal translocation is the cause of leukemia and other cancers she discovered the Philadelphia chromosomes and she won the National Medal of Science the Presidential Medal of Freedom and the last cohort so I now want to just say a few comments in the remaining time about some statistical approaches and we'll start with blind studies you may not realize that the first person to use a blind study was Benjamin Franklin in 1784 King Louie the sixteenth of France asked Franklin to study a problem he had with his people in Paris were hugging the trees in Versailles and they were convinced it made them better cured all their ills and so the King didn't like that so he as Franklin – appointed committee and he did and on that committee were all sorts of famous people such as guillotine of the knife and others and they went to the Versailles and hugged the trees this committee and they couldn't decide whether it made any difference so they decided to bring in volunteers blindfold them and give them objects to hold some of which were tree limbs and pieces of the Versailles trees and they concluded that it didn't work and but Franklin was phenomenally observant and he identified the placebo effect and this was also the discovery of the placebo effect so the first paper using blinded approach to do clinical research and identifying a placebo effect was done by Franklin and the paper I have a copy of it if anybody's interested is shown here on the right probably didn't know that about Franklin now placebo our blinding was sort of ignored then but a few hundred years later torold Solman who was a great statistician suggested a placebo control and blinded observer might be a solution to investigator bias and that was about 1930 and then of course blindfold tests were widely used by advertisers and consumers groups in the 1930s and 1940s the first use of statistics was a borrowed idea birds and sir Ronald Aylmer Fisher who applied statistics for agriculture use and introduced the application of statistics and experimental design and for farming and plant fertility the concept of randomizations and analysis of variance were developed by him and then it was later applied to medicine the first modern example of a controlled clinical trial was done by Sir Austin Bradford in 1948 who did a study to show that streptomycin was an effective drug for pulmonary tuberculosis this was a beautiful study and clearly showed the importance of a randomized control group to prove that streptomycin was an effective therapy for TB okay medical ethics is a you've probably heard of gerhard hansen who discovered the cause of leprosy in 1874 but this claim was not well received at the time and he became desperate to prove that it really was the cause of leprosy so without telling some nurses he inoculated them with live leprosy bacillus and he gave receipt and he was sued and he lost and he was removed from his position but look for reasons that aren't completely clear he was so well recognized in his institution that he was allowed to still work but he committed what would be considered a grave violation of ethical principles in 1898 William Osler at a meeting said to Giuseppe Santorelli who had discovered the etiologic agent for yellow fever and did somewhat similar to what Hansen did he injected this agent into volunteers without telling them and gave them yellow fever he said to deliberately inject the poison of No a degree of variola see into human being unless you obtain a man's consent is criminal and that was the end of Santa Ellie's career unlike cancer so that was sort of the beginning of informed consent and I'm gonna jump ahead to 1953 the day shortly but within days of the clinical Center opening here at NIH when the Medical Board in their very first meeting on dr. Luther Terry who was chair of that board said that they had to provide each patient with a reasonable understanding of his role in a study project and the means of obtaining evidence for such understanding and consent and this policy at the clinical Center had a big effect it had a big effect on Congress and the Harris Keifer Harris amendment to the FDA's law stipulated that subjects must be told whether a drug is being used for investigational purposes and the United States Surgeon General issued a policy saying that any federal money used to support research using drug development required review by an institutional review board to make sure that it was ethical and that was on all public health service grants in 1967 relatively recently the FDA required all new drug sponsors obtain informed consent for use of investigational drugs in humans and you're gonna hear about ethics and a history of ethics from Christine Grady and others and you'll learn more about the background and current policies so this is my last slide and I wanted to leave you with the message if you haven't figured it out that the business of clinical research isn't been an international business with great people literally in every culture and we're all the beneficiaries of that and what we do today I think is just capitalizing on what an awful lot of people have done before us so I hope the course that you're going to sit through and in the throughout the next weeks proves to be interesting to you and helpful you're gonna get learn a lot about statistics and study design you're gonna learn about how to apply for money you're gonna learn how to review you're gonna learn about the ethical legal and social issues and the faculty are phenomenally dedicated and hope that you enjoy the course as much as we enjoy teaching it now please fill out your forms as you hear the lectures and help us make the course better each year so thank you very much if there are any questions here in this room I'd be happy to entertain them if not

8 comments

  1. The years of birth and death of Semmelweis are different to Wikipedia. According to this presentation, Semmelweis died at the age of 16! According to Wikipedia, he died at the age of 47. https://en.wikipedia.org/wiki/Ignaz_Semmelweis

  2. I found the lecture very interesting despite being long. The quote of Isaac Newton really drives home the point that modern-day Scientists should appreciate the foundation provided by the early ones.
    Particularly striking was the effort by early Scientists to proffer solutions to problems sometimes at the expense of their comfort and life too! Case in point, are men like Emperor Shen Nung, reputed to have eaten 365 medicinal plants in the course of his life and died!
    I also found the clinical experiment by James Lind quite remarkable as he used only 12 sailors to make scientific assertions that proved to be life-saving with positive impact on mankind.

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