History of Clinical Research: History of Clinical Research Kitikrishna Learning Objectives: Learning Objectives A Brief History of clinical trials Nazi Trials- Nuremberg code Tuskegee syphilis study – Belmont report Sulfanilamide tragedy Thalidomide tragedy Clinical Trial Can be traced back to: Clinical Trial Can be traced back to Bible Works of Chanakya Ancient Chinese & Egyptian Medicine Ancient Chinese Medicine 2737 B.C. : 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. James Lind : 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 therapies for scurvy. James Lind – Experimental Design : 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 Compared to patients in the other 5 arms of the trial; no placebo group Semmelweis, 1848 - 1863 : Semmelweis , 1848 - 1863 Studied puerperal sepsis in Vienna over the protestations of his chief Noted that the sepsis rate was three times higher in Division 1 than in Division 2; Divisions identical except medical students taught 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 . Semmelweis - Experimental Design : 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%. His chief did not believe his data; one year later he was fired. Semmelweis - Experimental Design : Semmelweis - Experimental Design He returned to Budapest, Hungary where he was placed in charge of an obstetrical unit plagued with an epidemic of puerperal sepsis. He repeated his earlier experiment and again the mortality rate declined precipitously (mortality remained less than 1% during his six-year tenure vs. 10 to 15% in Vienna and Prague). Slide 11: 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. Joseph Lister (1827-1912) : Joseph Lister (1827-1912) Born in Essex, England Lister’s careful trials with antiseptics were the beginning of the end of post-op sepsis. The carbolic sprays he advocated were initially messy and unpleasant. Louis Pasteur (1822-1895) : 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 Torald Sollmann: Torald Sollmann Torald Sollmann suggested a placebo control and blinded observer as a solution to investigator bias as early as 1930 John Snow (1813-1858) : 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) Statistics illustrate connection between quality of water source and cholera cases Study was major event in public health history Sir Austin Bradford Hill: Sir Austin Bradford Hill During World War II, Sir Austin Bradford Hill designed what many regard as one of the first truly modern clinical trials because Hill employed the technique of randomization in assigning the study participants to the treatment groups. The newly developed drug streptomycin looked promising as a treatment for tuberculosis , but the drug had not yet been produced on a widespread scale. Given this shortage, Hill and his associates felt that it was ethical to carry out this trial—with a control group of patients who would not receive the drug--in order to definitively answer the scientific question of the drug’s merit. Slide 18: Nazi human experimentation Slide 19: German physicians conducted a series of pseudoscientific medical experiments on thousands of concentration camp prisoners without their consent. Most prisoners died or were permanently crippled as a result. Experiments on twins: Experiments on twins Led by Josef Mengele Experiments on twin children To show the similarities and differences in the genetics of twins Twins were arranged by age and sex Experiments ranged from injection of different chemicals into the eyes of twins to see whether it would change their color to literally sewing twins together in attempts to create conjoined twins Freezing experiments: Freezing experiments Experiments with the intent of discovering means to prevent and treat hypothermia Subjects forced to endure a tank of ice water for up to five hours. Prisoners placed naked in the open air for several hours with temperatures as low as -6°C (21ºF). Besides studying the physical effects of cold exposure, the experimenters also assessed different methods of rewarming survivors. Malaria experiments: Malaria experiments Infected by mosquitoes or by injections of extracts of the mucous glands of female mosquitoes. After contracting the disease-treated with various drugs to test their relative efficiency. Over 1,000 people used in the experiments -more than half dead Mustard gas experiments: Mustard gas experiments Test subjects were deliberately exposed to mustard gas and other vesicants, which inflicted severe chemical burns. The victims' wounds were then tested to find the most effective treatment for the mustard gas burns Sulfonamide experiments: Sulfonamide experiments Experiments to investigate - effectiveness of sulfonamide, a synthetic antimicrobial agent. Wounds inflicted on the subjects were infected with bacteria such as Streptococcus , Clostridium bacteria. Circulation of blood was interrupted by tying off blood vessels at both ends of the wound -to create a condition similar to that of a battlefield wound. Infection was aggravated by forcing wood shavings and ground glass into the wounds. The infection was treated with sulfonamide and other drugs to determine their effectiveness. Sea water experiments: Sea water experiments Experiments to study various methods of making sea water drinkable. People were deprived of food and given nothing but sea water to drink by Dr. Hans Eppinger , leaving them gravely injured. They were so dehydrated that others observed them licking freshly mopped floors in an attempt to get drinkable water. Sterilization experiments: Sterilization experiments To develop a method of sterilization which would be suitable for sterilizing millions of people with a minimum of time and effort. IV injections of solutions speculated to contain iodine and silver nitrate were successful - unwanted side effects- vaginal bleeding, severe abdominal pain, and cervical cancer. Radiation treatment became the favored choice of sterilization.. Many suffered severe radiation burns Slide 28: Experiments with poison Incendiary bomb experiments High altitude experiments Slide 29: Many of the subjects died as a result of the experiments conducted by the Nazis, while many others were murdered after the tests were completed to study the effect post mortem. Slide 30: August 19, 1947, the judges delivered their verdict in the "Doctors' Trial" against Karl Brandt and several others. Accused had argued that their experiments differed little from pre-war ones and that there was no law that differentiated between legal and illegal experiments In response, Dr. Leo Alexander and Dr. Andrew Conway Ivy drafted a ten point memorandum entitled Permissible Medical Experiment that went on to be known as the Nuremberg Code Slide 31: Syphilis Study at Tuskegee Slide 32: In the late 1920’s, syphilis was a terrible disease -no effective treatment available 1932, the U.S. Public Health Service began an investigation into the natural history of this dread disease location chosen for the study – Tuskegee, Macon County -in Alabama, a place that had the highest syphilis prevalence in the country. The populace was largely of African-American descent. Slide 33: Thus began the longest observational study in medical history: “ The Tuskegee Study of Untreated Syphilis in the Negro Male” (1932 – 1972) Slide 34: Study initially involved 600 black men – 399 with syphilis, 201 who did not have the disease. The study was conducted without patients' informed consent. Researchers told the men they were being treated for "bad blood," a local term used to describe several ailments, including syphilis, anemia, and fatigue. None were told that they were infected with syphilis Patients did not receive the proper treatment needed to cure their illness. In exchange for taking part in the study, the men received free medical exams, free meals, and burial insurance. Although originally projected to last 6 months, the study actually went on for 40 years. Slide 35: Over the course of the project, PHS officials not only denied study participants treatment, but prevented other agencies from supplying treatment. Even when penicillin became the drug of choice for syphilis in 1947, researchers did not offer it to the subjects Slide 36: In 1972 Peter Buxton told the story of the Tuskegee Study to an Associated Press reporter Slide 37: The Assistant Secretary for Health and Scientific Affairs appointed an Ad Hoc Advisory Panel to review the study. Panel concluded that the Tuskegee Study was "ethically unjustified"--the knowledge gained was sparse when compared with the risks the study posed for its subjects. In October 1972, the panel advised stopping the study at once. Slide 38: Lawsuit was filed on behalf of the study participants and their families. In 1974, a $10 million out-of-court settlement was reached. As part of the settlement, the U.S. government promised to give lifetime medical benefits and burial services to all living participants. Belmont Report: Belmont Report 1979 Belmont Report (issued by U.S. National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research) Principle of Respect: Recognized autonomy of humans and requires clear informed consent. Principles of Beneficence : Research mush be shown to be beneficial and reflect the Hippocratic idea of do no harm. Principle of Justice : The benefits to some must be balanced against the risks of subjects Slide 40: Tuskegee Syphilis study has become a powerful symbol of racism in medicine, ethical misconduct in human research, and government abuse of the vulnerable. On May 16, 1997, President, Bill Clinton apologized on behalf of the United States government to the surviving participants of the study. The last study participant died in January 2004 Slide 41: Sulfanilamide Tragedy Slide 42: Sulfanilamide, included in a class of drugs known as sulfonamides, or sulfa drugs, was praised in the 1930s as the first product to successfully treat bacterial infections. Gerhard Domagk- won Nobel Prize in 1932 for discovering the antibacterial effects of the first sulfonamide drug, Swiss pharmacologist Daniel Bovet, acknowledged for identifying that sulfanilamide killed strains of Streptococcus bacteria, won Nobel Prize in 1936. Slide 43: "There has probably never been a single drug before or since that has had such a quick acceptance," said historian Gene Davis in a documentary film scheduled to air on the History Channel on December 11. "It was truly the first miracle drug of the 20th Century." So, What went wrong………?: So, What went wrong………? Sulfanilamide, a drug used to treat streptococcal infections, had been shown to have dramatic curative effects and had been used safely for some time in tablet and powder form. Pharmaceutical companies struggled with how to successfully liquefy the drug so that the product could be marketed for children and patients who preferred to take their medications in liquid forms. In 1937, Harold Watkins, chief chemist for pharmaceutical manufacturer S.E. Massengill Co. in Bristol, Tennessee, discovered that he could use an industrial chemical called diethylene glycol (DEG) as a dissolving agent for sulfanilamide Slide 45: Watkins also added raspberry flavoring and red coloring to the product, which Massengill marketed as Elixir Sulfanilamide, so that the medication would be more appealing for children. Taste of Raspberries, Taste of Death…: Taste of Raspberries, Taste of Death… DEG, a chemical normally used as an antifreeze, is a deadly poison, and Watkins and his company failed to test the product for safety before shipping 633 of them But days after taking the first dose of the elixir, several patients died of kidney failure Slide 47: The AMA asked for samples of the drug and then wired the Massengill Co., requesting the composition of the compound. The AMA laboratory isolated diethylene glycol as the toxic ingredient and immediately issued a warning, through newspapers and radio, that Elixir Sulfanilamide was toxic and deadly. Slide 48: Persistence of federal, state, and local health agencies and the effects of the AMA and the news media, most of the elixir was recovered. Of 240 gallons manufactured and distributed, 234 gallons and 1 pint was retrieved; the remainder was consumed and caused the deaths of the victims. It caused the deaths of more than 100 people. Harold Watkins committed suicide after learning of the effects of his latest concoction. Slide 49: Massengill Co. was charged with misbranding. "Elixir," FDA said, implied the product was an alcoholic solution whereas it was, in fact, a diethylene glycol solution and contained no alcohol. Congress responded to public outrage by passing the 1938 Food, Drug, and Cosmetic Act , which required that companies perform animal safety tests on their proposed new drugs and submit the data to the FDA before being allowed to market their products. Slide 50: Thalidomide Tragedy Thalidomide Disaster (1959-1960's) : Thalidomide Disaster (1959-1960's) Developed by a German company Gruenenthal , Thalidomide was originally intended to help pregnant women rest, and help reduce morning sickness. Unfortunately, the drug caused birth defects when consumed during pregnancy. Phocomelia: Phocomelia The most common and obvious was the shorted limbs known as phocomelia , which comes from the Greek and means seal limbed. In this condition, the long bones of legs or arms are shortened or missing. The hands and feet of the affected limbs appear flipper like. Other conditions seen were the addition of small vestigial extra limbs and occasional mental disorders. Slide 53: An estimated 12,000 children were born with this condition worldwide. Most of those births occurred in Europe and Africa Slide 54: US was fortunate to have Frances Oldham Kelsey, who refused to approve marketing of thalidomide in the U.S. because of weaknesses in the safety data, preventing thousands of birth defects. Slide 55: It is proving an effective treatment for certain cancers. It is also aiding patients suffering from leprosy. Kefauver Harris Amendment: Kefauver Harris Amendment The U.S. Kefauver Harris Amendment or "Drug Efficacy Amendment" is a 1962 amendment to the Federal Food, Drug, and Cosmetic Act. It introduced a requirement for drug manufacturers to provide proof of the effectiveness and safety of their drugs before approval, required drug advertising to disclose accurate information about side effects. Declaration of Helsinki: Declaration of Helsinki The Declaration of Helsinki is a statement of ethical principles developed by the World Medical Association to: "provide guidance to physicians and other participants in medical research involving human subjects" (Para 1, Declaration of Helsinki). This includes research on people, identifiable human material or identifiable data. The Declaration was first adopted in 1964 and has since undergone several revisions (1975, 1983, 1989, 1996, 2000, and in 2008) to accommodate advances in medical science and ethical problems. Slide 58: The Declaration includes principles on: Safeguarding research subjects Informed consent Minimising risk Adhering to an approved research plan/protocol The Declaration is considered a fundamental document in the ethics of healthcare research. As a result, the principles have been embodied in subsequent UK and international guidance and regulations. Slide 59: Conclusion (1) The history of clinical research can be traced to all cultures. (2) The future requires information exchange to maximize progress in health care. (3) “What’s past is prologue” (William Shakespeare, The Tempest) Thank you!