Ricerca Clinica: 5 mila anni di storia

Quando ho visto questa cronistoria non credevo ai miei occhi. Le fondamenta della Ricerca Clinica risalgono alla notte dei tempi!

Ecco una interessantissima panoramica di quello che e’ successo a partire dal 2737 a.C. Vale davvero la pena leggerlo tutto:

3000 anni prima di Cristo:

• 2737 BCE: Shen-nung pen ts’ao ching (Divine Husbandman’s Medical Materials) describes 365 medicines derived from minerals, plants and animals; believed to be authored by Shen Nung, the “father of Chinese medicine.”
• ~600 BCE: Daniel designs and participates in a controlled nutritional study in the court of Nebuchadnezzar II, King of Babylon. Study is reported in the Old Testament sometime later.
• 400-200 BCE: Charaka Samhita, a textbook in verse of Ayurvedic medicine, is written in India.
• ~400 BCE: Hippocratic Oath defines responsibilities of physicians to their patients (with no mention of experimentation). Hippocrates, who lived in Greece probably sometime between 460 and 380 BCE, probably did not write the oath.
• 280 BCE: City of Alexandria gives Greek physician Herophilus and his colleague Erasistratus permission to cut into and look inside a prisoner condemned to death, for purposes of scientific investigation.
• ~200 BCE: Sushruta Samhita, a textbook in verse of Ayurvedic surgery, is written in India.
• 137 BCE: Attalus III (Philometer), King of Pergamum, tests the effects of extracts from poisonous plants by offering them in beverages to his guests.

Primo Millennio dopo Cristo:

• 162: Galen moves to Rome, where he develops the science of experimental physiology.
• ~550: Babylonian Talmud (Niddah (30b)) tells story about Cleopatra, who, to settle an argument between two rabbis about how long it takes for male and female fetuses to develop, had slave girls impregnated and operated on at specified times to examine the development of the fetuses. The investigators reported that boys developed in 40 days and girls took 80 days.
• ~930: Rhazes (Bakr Muhammad ibn Zakariyya al-Razi) publishes Kitab al-Hawi fi al-tibb (The Comprehensive Book of Medicine), in which he describes treating one group of patients with early symptoms of meningitis with bloodletting and another without, thereby determining that bloodletting prevents development of the disease.

Secondo Millennio dopo Cristo:

• ~1030: Avicenna (Abū ‘Alī al-Husayn ibn ‘Abd Allāh ibn Sīnā), a Persian physician, publishes The Book of the Canon of Medicine (Qanun fi al-Tibb), setting forth seven rules for systematically evaluating the effect of drugs on diseases.
• 1061: Chinese government administrator Song Su publishes Ben Cao Tu Jing (Atlas of Materia Medica), a pharmacopeia.
• ~1175: Moses Maimonides, physician, writes prayer, including the line: “Inspire me with love for my art and for Thy creatures. Do not allow thirst for profit, ambition for renown and admiration, to interfere with my profession, for these are the enemies of truth and of love for mankind and they can lead astray in the great task of attending to the welfare of Thy creatures.”
• ~1260: Roger Bacon, English scientist, philosopher, and Franciscan monk, writes that, “it is more difficult [for a physician] to [experiment] in [medical] science than in any other…because of the nobility of the material in which he works; for that body demands that no error be made in operating upon it….”
• 1500s: Paracelsus (Theophrastus Bombastus von Hohenheim), who traveled widely in Europe, teaches to investigate nature “not by following that which those of old taught, but by our own observation of nature, confirmed by… experiment and by reasoning thereon.”
• 1537: In the middle of a siege battle, physician Ambroise Paré of France runs out of boiling oil, the usual remedy for treating open wounds at the time, and discovers that treatment with a tincture of egg yolk, oil of rose, and turpentine reduces pain, swelling and mortality.
• 1662: Jan Baptist van Helmont, a Flemish medicinal chemist and disciple of Paracelsus, proposes a randomized test of blood-letting with 200 to 500 fever and pleurisy patients, backed by his wager of 300 florins against blood-letting, which is not accepted.
• 1667: Samuel Pepys records in his diary an experiment in which the Royal Society of London pays Arthur Coga 20 shillings to allow 12 ounces of sheep blood to be “let into his body,” with no apparent ill effects.
• 1721: Sir Hans Sloane, physician to the King of England, hires Charles Maitland to inoculate six prisoners with smallpox. All were infected and survived to gain the reward of release from Newgate prison. Maitland subsequently demonstrated immunity for one of them.
• 1747: James Lind of Scotland conducts a study of the treatment of scurvy, assigning 12 sailors, in pairs, to citrus and five other potential treatments.
• ~1750: Voltaire states: “The art of medicine consists of amusing the patient while nature cures the disease.”
• 1759: Francis Home of Scotland tests measles “vaccine” (blood from a measles patient) in 12 children.
• 1760: Anton Storck of Vienna tests the effect of hemlock in increasing doses on himself.
• 1764: Thomas Bayes of England publishes Baye’s Theorem for calculating conditional probabilities, establishing the statistical basis for adaptive trials.
• 1767: English court rules in Slater v. Baker & Stapleton that informed consent is required prior to experimental medical treatment. Baker and Stapleton set and then rebroke Slater’s fractured but healing leg to test a new device.
• 1767: Prior to inoculating all the children at the Foundling Hospital in London, England for smallpox, Dr. William Watson conducts a vaccination trial with three groups of 10 children each. Two of the groups receive pre-and post-treatments; one does not.
• 1770: John Gregory, Scottish physician, writes “Observations on the Duties and Offices of a Physician and on the Method of Prosecuting Enquiries in Philosophy”, the first English-language book on bioethics.
• 1775: British physician William Withering identifies leaves from the foxglove plant as an ingredient in herbal remedies for dropsy (the accumulation of fluid in the lower extremities due to cardiac insufficiency). He later proves its effectiveness in experiments on numerous patients. The active ingredient is digoxin, a current treatment for congestive heart failure.
• 1784: Under appointment by Louis XVI of France, a commission led by Benjamin Franklin conducts placebo-controlled and single-blinded (literally, by blindfolding the subjects) studies of the use of magnetism to treat various ailments.
• 1796: Edward Jenner of England demonstrates that cowpox vaccination protects against smallpox by vaccinating and then exposing 12-year-old James Phipps to someone with smallpox.
• 1796: First patent on a medical device is issued, for Perkins Metallic Tractors, consisting of two pointed metal rods about three inches long, one iron and one brass, used as levers to draw toxic electricity from the body in the treatment of headache, rheumatism, deformities, etc.
• 1799: John Haygarth conducts placebo-controlled and single-blinded (with sham wooden “medical devices”) studies of the use of Perkins Metallic Tractors, consisting of iron and brass rods, to relieve pain.

XIX Secolo:

• 1800: Benjamin Waterhouse, one of three full-time professors at Harvard Medical School, successfully tests Edward Jenner’s cowpox vaccine on his son, then on six members of his household, and then on 19 children in a Boston hospital. He then creates a commercial monopoly on the vaccine in the United States. Partially as a result, he is expelled from the Harvard faculty in 1812.
• 1803: Thomas Percival of England publishes “Code of Ethics”, advising physicians to consult with colleagues before trying new remedies and treatments. Percival separately advises physicians not to inform the patient if the information would adversely affect the patient, the patient’s family, or the community.
• 1809: Scottish physician Alexander Lesassier Hamilton and two other army physicians conduct a clinical trial in which 366 sequentially-admitted sick soldiers are assigned in rotation to three physicians. One physician uses bloodletting; the other two do not. Mortality rate is 29% with bloodletting and 2% without.
• 1813: Vaccine Act regulates vaccines.
• 1818: Scottish physician Alexander MacLean, describes medicine practiced without systematic testing as,”a continued series of experiments upon the lives of our fellow creatures.”
• 1820: Eleven physicians meet in Washington D.C. to create the U.S. Pharmacopeia, a compendium of standard drugs.
• 1824: Royal Society for the Prevention of Cruelty to Animals is founded in London.
• 1830: English physician J.W. Willcock writes: “When an experiment is performed with the consent of the party subjected to it after he has been informed that it is an experiment, the practitioner is answerable neither in damages nor on an original proceeding. But if the practitioner performs his experiment without giving such information and obtaining consent he is liable to compensate in damages any injury.”
• 1831: English physiologist Marshall Hall proposes principles to govern animal experimentation.
• 1831: Physician Herrmann compared homeopathic, allopathic and placebo treatments in three wards in the Regional Military Hospital in St.Petersburg, Russia, finding that the placebo ward yielded the best results.
• 1832: “Placebo” takes on its current meaning of a treatment that has no medical value except psychologically.
• 1832: Physician William Beaumont signs a contract with Alexis St. Martin, a long-term research subject with a permanent gastric fistula (hole to his stomach), whereby Mr. Martin enlists in the Army for one-year – with no military duties – and receives payment of $150.
• 1833: Physician William Beaumont publishes research ethical guidelines, including voluntary consent and right to withdraw.
• 1836: Army Surgeon General establishes library, later to become the National Library of Medicine, the world’s largest.
• 1836: French physician Pierre-Charles-Alexandre Louis conducts a quantitative epidemiologic study of the treatment of pneumonia with bloodletting. (Bloodletting may relieve pulmonary edema – excess fluid in the lungs.) He finds that the duration of the disease is shorter in patients who are bled sooner rather than later, with the caveat that mortality is 76% higher.
• 1845: Max Simon writes that experimentation is necessary to advance science, but under no circumstances could a physician “sacrifice the interests of the individual to those of society” or to “scientific speculation.”
• 1847: American Medical Association adopts a code of ethics, including the “sacred duty” to avoid disclosures that would discourage or depress the patient.
• 1848: Drug Importation Act requires U.S. Customs Service to inspect all medications entering U.S. ports for quality, purity, and fitness for medical purposes.
• 1849: In “Physician and Patient,” Worthington Hooker discusses the doctor-patient relationship, writing that “the good, which may be done by deception in a few cases, is almost as nothing, compared with the evil which it does in many cases.”
• 1851: American Pharmaceutical Association founded, later renamed the American Pharmacists Association.
• 1852: Physician Marion Sims, the “father of gynecology,” reports in the Journal of the American Medical Sciences that on his thirtieth attempt with slave women – probably without their informed consent and perhaps without their consent at all – he successfully repaired a vesicovaginal fistula (without anesthesia).
• 1862: “Report of the Committee on the Action of Medicines” describes the findings of a “collective investigation,” a British survey of physicians about a medical treatments.
• 1862: President Abraham Lincoln appoints Charles M. Wetherill, a chemist, to the Department of Agriculture, the first step towards formation of the Bureau of Chemistry, predecessor of the Food and Drug Administration.
• 1865: In “An Introduction to the Study of Human Experimentation,”” French physiologist Claude Bernard states “”Never perform an experiment that might be harmful to the patient even though highly advantageous to science or the health of others.”
• 1866: American Society for the Prevention of Cruelty to Animals is founded.
• 1868: Pharmacy Act requires testing and registration of persons who dispense drugs such as morphine, cocaine, and barbiturates, but not patent medicines that may contain those drugs.
• 1871: Court rules in Carpenter v. Blake that the physician must fully inform the patient before departing from standard medical practice.
• 1875: UK Sale of Food and Drugs Act prohibits sale of drugs not of the proper nature, substance and quality.
• 1876: Britain passes Cruelty to Animals Act and Animals (Scientific Procedures) Act, protecting animals used in research.
• 1877: American Humane Association is founded to protect animals and, later, children.
• 1879: S. Potter and Eugene F. Storke conduct double-blind experiment at the Milwaukee Academy of Medicine, comparing a homeopathic remedy to a sugar pill.
• 1880: German physician Gerhard Armauer Hansen, co-discoverer of the leprosy bacillus, loses his license to practice medicine after deliberately infecting the eye of a patient with leprosy bacilli.
• 1881: British Medical Association establishes Collective Investigation Committee, which sponsors inquiries into the natural history of disease.
• 1882: State of West Virginia licenses physicians.
• 1883: Caroline Earl White founds the American Anti-Vivisection Society to protect animals from experimentation.
• 1883: Park-Davis is producing 20 botanical extracts, assayed for consistent chemical content and thus therapeutic effect.
• 1884: Possibly after successful experiments with dogs, Louis Pasteur first tests an antidote to rabies on an infected child, Joseph Meister, but only after pleadings from the child’s mother and consultations with two medical colleagues, who advise him that the child’s death is inevitable without treatment. Meister later becomes a guard at the Institut Pasteur in Paris, and is shot defending Pasteur’s laboratory in World War II.
• 1886: Dr. Charles Francis Withington, in “The Relation of Hospitals to Medical Education,” advocates a “Bill of Rights” to “secure patients against any injustice from the votaries of science” because researchers “had no right to make any man the unwilling victim of such an experiment.”
• 1887: Marine Hospital Service establishes Hygienic Laboratory to monitor arriving ship passengers for cholera, yellow fever, and other infectious diseases. Dr. Joseph Kinyoun is the sole employee for at least 14 years.
• ~1890: Russian physician D. V. Dmitriev creates an informed consent form for a volunteer donating part of his thyroid gland for transplantation. The document includes sections on explanation, risks, benefits, voluntariness, cost and procedures.
• 1891: Canadian physician William Osler writes in Science Magazine, “A desire to take medicine is, perhaps, the great feature which distinguishes man from other animals.”
• 1895: Chemist Edwin E. Slosson writes in the New York Independent, “A human life is nothing compared with a new fact in science….the aim of science is the advancement of human knowledge at any sacrifice of human life….We do not know of any higher use we can put a man to.”
• 1896: Johannes Fibiger, Danish physician and later Nobel laureate, publishes results of randomized clinical trial of serum treatment of diphtheria. 584 subjects were randomized to the serum treatment group or standard-treatment group based on their admission to Blegdamshospitalet on alternate days.
• 1896: William Henry Welch begins publication of the Journal of Experimental Medicine.
• 1898: American Journal of Physiology begins publication.
• ~1899: Canadian physician William Osler condemns Giuseppi Sanarelli’s Yellow Fever experiments: “To deliberately inject a poison of known high degree of virulence into human beings, unless you obtain that man’s sanction, is not ridiculous, it is criminal.”

XX Secolo:

• 1900: “Instructions of the Prussian Minister of Culture to the Directors of Clinics, Polyclinics, and Other Health Care Institutions” Prussia prohibits medical interventions for other than therapeutic purposes without informing the subject of potential adverse consequences and obtaining consent.
• 1900: German bacteriologist Albert Neisser, discoverer of the gonococcus bacillus and co-discoverer of the leprosy bacillus, is fined 300 marks for testing a potential syphilis vaccine on five women and three girls.
• 1900: Walter Reed uses written consent form (in English and Spanish) in a study of yellow fever transmission at Camp Lazear in Cuba; stipend is $100 plus an additional $100 if the subject is infected by the experiment.
• 1900: While Walter Reed is traveling, Yellow Fever Board physician James Carroll survives yellow fever after deliberately exposing himself to mosquitoes carrying the virus; physician Jesse Lazear dies after deliberate or accidental exposure.
• 1901: USDA Division of Chemistry is promoted to Bureau of Chemistry, with a new emphasis on drugs.
• 1902: After 13 children in St. Louis, Missouri and nine in Camden, New Jersey die from diphtheria antitoxin contaminated with tetanus spores in 1901, Biologics Control Act authorizes Hygienic Laboratory to regulate the production of vaccines and antitoxins.
• 1902: Albert Moll’s book, “Medical Ethics”, recommends that advisory boards of physicians, lawyers and other learned men consider the ethical aspects of planned human experiments.
• 1902: Hygienic Laboratory launches three formal research programs under the direction of Ph.D.s.
• 1902: USDA Bureau of Chemistry creates Drug Laboratory.
• 1903: Italian civil authorities reprimand a physician for successfully infecting a man with malaria through inoculation.
• 1904: English mathematician Karl Pearson publishes meta-analysis on data from five small independent samples to compute a pooled estimate of correlation between enteric fever vaccination and mortality.
• 1905: American Medical Association establishes Council on Pharmacy and Chemistry to set standards for drug manufacturing and advertising, and fight against quack patent medicines. (Operational through 1955.)
• 1905: Samuel Adams Hopkins publishes first article in “The Great American Fraud,” an 11-part expose of patent medicines in Collier’s Weekly.
• 1906: “The Jungle,” by Upton Sinclair, publicizes lack of purity in meat products, leading to passage of the Pure Food and Drug Act.
• 1906: Arthur J. Cramp, MD, joins the editorial staff of the Journal of the American Medical Association and begins publishing regular items about medical fraud.
• 1906: In “Book on the Physician Himself,” Daniel Webster Cathell advises doctors to “be careful never to speak of anything you do for a patient as an experiment… for every body is more or less opposed to physicians ‘trying experiments’ upon themselves or theirs.”
• 1906: Pure Food and Drug Act prohibits adulteration or misbranding of drugs, with the burden of proof on the FDA.
• 1906: Richard Pearson Strong, head of the Philippine Biological Laboratory, inoculates 24 inmates of Manila’s Bilibid Prison with an experimental cholera vaccine contaminated with plague bacilli, resulting in 13 deaths.
• 1907: Canadian physician William Osler, in “The Evolution of the Idea of Experiment,” writes “For man absolute safety and full consent are the conditions which make such tests allowable. We have no right to use patients entrusted to our care for the purpose of experimentation unless direct benefit to the individual is likely to follow.”
• 1907: Dr. Albert Leffingwell, in “Illustration of Human Vivisection,” writes “At the beginning of a new century we are confronted by great problems. One of these is human vivisection in the name of scientific research. We appeal, then, to the medical press of America to break that unfortunate silence which seems to justify or, at least, to condone it. Now and henceforth, will it not join us in condemning every such vivisector of little children, every such experimenter upon human beings?”
• 1907: Joseph Goldberger reviews 26 published studies reporting data on the frequency of urinary infection in cases of typhoid fever.
• 1909: American Humane Society reports that the U.S. has 104 associations devoted to preventing cruelty to animals, 45 to children, and 185 to both, with combined participation of approximately 42 million people.
• 1910: Rockefeller Institute Hospital opens, devoted entirely to clinical research.
• 1911: In U.S. v. Johnson, the Supreme Court rules that the 1906 Food and Drugs Act does not prohibit false therapeutic claims but only false and misleading statements about the ingredients or identity of a drug.
• 1912: Sherley Amendment prohibits labeling medicines with false therapeutic claims intended to defraud the purchaser.
• 1912: U.S. Supreme Court rules in “”Dr. Johnson’s Mild Combination Treatment for Cancer” case that Pure Food and Drug Act does not prohibit false therapeutic claims but only false and misleading statements about the ingredients or identity of a drug.
• 1913: George Bernard Shaw uses the term “guinea pig” to compare the role of children in child-rearing to the role of human subjects in medical experiments.
• 1913: UK establishes Medical Research Committee and Advisory Council.
• 1914: Mary Schloendorff, a patient at New York Hospital, consents to an examination under ether of a fibroid tumor, but prohibits the doctor from performing an operation. Once the patient is unconscious from the ether, the doctor removes the tumor, and the patient later develops gangrene, requiring the amputation of several fingers. In the case of Schloendorff v. Society of New York Hospital, future Supreme Court Justice Benjamin Cardozo writes “Every human being of adult years and sound mind has a right to determine what shall be done with his own body; and a surgeon who performs an operation without his patient’s consent commits an assault, for which he is liable in damages.”
• 1915: Public Health Service researcher Joseph Goldberger conducts study on 11 inmates of Rankin Prison in Mississippi that demonstrates the role of diet in pellagra, a disease caused by a deficiency of the vitamin niacin. The inmates recover and receive pardons for their participation.
• 1919: Amendments to Biologics Control Act require submission of product samples for government inspection and approval prior to distribution.
• 1919: UK Medical Research Committee and Advisory Council is renamed Medical Research Council (MRC).
• 1920: UK Medical Research Council opens central research institute, later named the MRC National Institute for Medical Research.
• 1923: The “Friends of Medical Progress,” later renamed the “American Association for Medical Progress,” is founded in Boston to support medical research.
• 1923: R.A. Fisher and W.A. MacKenzie perform statistical randomization in an agricultural experiment.
• 1925: Educator Abraham Flexner writes, “Research can no more be divorced from medical education than medical education can be divorced from research.”
• 1927: Food and Drug Administration is created from USDA Bureau of Chemistry.
• 1928: Cooperative Clinical Group is formed to perform multi-site research on syphilis.
• 1930: NIH assigns newly-established Division of Biologics Control responsibility for regulating biologics.
• 1930: Paul Martini of Germany employs single-blind design in drug studies.
• 1930: Pharmacologist Torald Sollman writes, “Apparent results must be checked by the ‘blind test,’ i.e., another remedy or a placebo, without the knowledge of the observer, if possible.”
• 1930: Ransdell Act renames Hygienic laboratory the National Institute of Health (NIH) and expands its functions.
• 1931: “Circular of the Minister of the Interior of the German Reich Concerning Guidelines for Innovative Therapy and Human Experimentation” differentiates between therapeutic research, primarily intended to benefit the patient, and non-therapeutic research, primarily intended to advance knowledge.
• 1931: After 72 of 251 infants vaccinated in 1929-1930 in Lubeck, Germany for tuberculosis die because the vaccine was accidently prepared with virulent bacteria, the German government enacts “Regulation on New Therapy and Experimentation”, requiring human experiments to be preceded by animal experiments.
• 1931: Great Britain’s Medical Research Council establishes Therapeutic Trials Committee “to consider applications by commercial firms for the examination of new products, submitted with the available experimental evidence of their value, and appropriate clinical trials will be arranged in suitable cases.”
• 1931: J.B. Amberson, B.T. McMahon, and M. Pinner publish negative results of matched-pair randomized, placebo-controlled clinical trial, comparing sanocrysin (sodium gold thiosulphate) to distilled water for the treatment of pulmonary tuberculosis.
• 1933: German Law on Animal Protection requires government approval for experiments that may cause appreciable pain or damage to animals.
• 1933: Isaac Starr, Leon Colins, and Francis Clark Wood publish “Studies of the Basal Work and Output of the Heart in Clinical Conditions” in the Journal of Clinical Investigation, explaining statistical concepts like standard deviation and correlation coefficients.
• 1935: Michigan Supreme Court rules in Fortner v. Koch that treating a patient in a controlled clincal trial that does not “vary too radically” from accepted practices does not impose the standard of strict liability (without fault) on the investigator, provided the subject consented.
• 1936: In Russia, Scientific Medical Council of the People’s Commissariat of Health Care adopts regulations governing the development of new drugs and procedures with human research subjects, addressing issues of risk, harm, consent and assent, and prior animal studies.
• 1937: Austin Bradford Hill of the U.K. recommends randomization by alternately assigning subjects in clinical trials in “Principles of Medical Statistics.”
• 1937: National Institutes of Health awards extramural research grants for clinical trials.
• 1938: Food, Drug, and Cosmetic Act requires pharmaceutical companies to prove drug safety.
• 1938: H.S. Diehl, in “Cold Vaccines: An Evaluation Based on a Controlled Study” describes the use of a saline solution as placebo.
• 1938: Sales of Elixir Sulfanilamide by the Massengill Company are stopped after a toxic ingredient, diethylene glycol, kills 107 people, mostly children, on the basis that the medicine was misbranded an elixir, and the alcohol required of an elixir was absent. Scandal leads to passage of the Food, Drug, and Cosmetic Act.
• 1940: FDA is transferred from USDA to the Federal Security Agency, which becomes the Department of Health, Education, and Welfare in 1953.
• 1941: Office of Scientific Research and Development establishes Committee for Medical Research to fund and coordinate research on military medical problems.
• 1943: U.S. War Department establishes “Guinea Pig Units” to use volunteers recruited by the National Service Board for Religious Objectors for studies of radiation exposure and other wartime health hazards.
• 1944: Biologic Control Act is amended to require biological product – not just establishment – licensing.
• 1944: British Medical Research Council publishes results in the Lancet of a multicenter, placebo-controlled trial of the antibiotic patulin to treat the common cold.
• 1944: Public Health Service Act authorizes NIH to conduct clinical research.
• 1946: American Medical Association adopts code of ethics for research on human subjects that requires informed consent.
• 1946: British Medical Research Council begins placebo-controlled, randomized clinical trial of whooping-cough vaccination, published in 1951.
• 1946: Nuremberg Code, the first internationally-recognized code of ethics for human research, requires voluntary and informed consent, minimizing risks to subjects, and results that are valuable to society.
• 1947: Carroll Wilson, General Manager of Atomic Energy Commission (AEC), uses the term “informed consent” in a letter to Robert Stone about AEC-sponsored human experiments using radioactive isotopes.
• 1947: NIH issues over $4 million in research grants.
• 1948: Andrew Ivy publishes “The History and Ethics of the Use of Human Subjects in Medical Experiments.”
• 1948: Austin Bradford A. Hill, Philip D’Arcy Hart, and Marc Daniels of the U.K. publish paper in the British Medical Journal on a clinical trial for tuberculosis treatment with streptomycin that uses statistically determined sample sizes and random number sampling for assignment of subjects.
• 1948: United Nations General Assembly adopts Universal Declaration of Human Rights, including the right to “security of person.”
• 1948: World Medical Association updates and clarifies Hippocratic Oath in Declaration of Geneva.
• 1949: FDA publishes first guidance to industry, “Procedures for the Appraisal of the Toxicity of Chemicals in Food.”
• 1949: Public Health Service issues research grants, including $29,000 to John H. Gibbon, Jr. for development of a heart lung machine.
• 1949: World Medical Association adopts “International Code of Medical Ethics,” stating that “a doctor owes to his patient complete loyalty.”
• 1950s: Double-blind experimental design becomes popular for drug studies.
• 1951: Armed Forces Medical Policy Council replaces Office of Medical Services to develop and review Department of Defense medical and health policies, plans and programs, including human research, and is replaced in turn by the Assistant Secretary of Defense (Health & Medicine) in 1953.
• 1951-1962: Department of Defense exposes over 200,000 enlisted men to radiation during atmospheric tests of atomic bombs in Nevada.
• 1951: Durham-Humphrey Amendment requires that drugs unsafe for self-medication be labeled for sale by prescription only.
• 1951: NIH starts randomized clinical trial on the treatment of rheumatic heart disease.
• 1952: Air Force adopts AFAR 80-22 regulations governing clinical research at its medical facilities and requiring that the School of Aviation Medicine Research Council approve human experiments.
• 1952: Donald Mainland publishes textbook “Elementary Medical Statistics.”
• 1952: NIH Clinical Center Medical Board’s Clinical Research Committee, the first IRB, meets for the first time.
• 1953: NIH opens Warren Grant Magnuson Clinical Center hospital for intramural research, with “Guiding Principles in Medical Research Involving Humans,” requiring Clinical Research Committee to review the use of any nonstandard, hazardous procedures, as well as healthy “normal volunteers.”
• 1953: Secretary of Defense Charles E. Wilson signs a top-secret memorandum adapting the Nuremburg Code, with addition of written and witnessed consent, for its experimental research in the fields of atomic, biological and chemical warfare. Top-secret classification limits use of the new rules.
• 1954: World Medical Association adopts “Resolution on Human Experimentation,” broader in scope than the Nuremburg Code, emphasizing the investigator’s responsibility over the subject’s willingness (informed consent).
• 1955: C. Gordon Zubrod leads the creation of cancer cooperative groups, supported by the Cancer Chemotherapy National Service Center (CCNSC) at NIH.
• 1955: National Cancer Institute conducts randomized cancer trial on acute leukemia and solid tumors.
• 1955: Public Heath Council in The Netherlands adopts human experimentation code.
• 1957: In Salgo v. Leland Stanford Jr. University Board of Trustees, American College of Surgeons uses the term “informed consent” while expressing its disapproval of the concept in an amicus brief.
• 1957: NIH issues over $100 million in research grants.
• 1960: Kansas Supreme Court, in Natan v. Kline, requires physicians to obtain informed consent from patients after disclosing the nature and purpose of the proposed treatment, its potential benefits and risks, and the alternative approaches available, along with their benefits and risks.
• 1960: U.S. Bureau of Prisons allows prisoners to enroll in clinical studies at NIH Clinical Center.
• 1961: Chemie Grunenthal withdraws thalidomide from the European and Canadian markets after it causes about 10,000 thalidomide birth defects, including about 17 in the U.S. The tragedy leads to passage of Kefauver-Harris Drug Amendments.
• 1962: Army Surgeon General Leonard D. Hatton clarifies in a meeting with Harvard Medical School representatives that the Army’s medical research principles, based on the Nuremburg Code, are guidelines, not rigid rules.
• 1962: Austin Bradford Hill publishes textbook “Statistical Methods in Clinical and Preventive Medicine.”
• 1962: FDA conducts first inspection of a clinical investigator.
• 1962: FDA initiates Drug Efficacy Study Implementation (DESI) program to review effectiveness of drugs marketed prior to 1962.
• 1962: Kefauver-Harris Drug Amendments to the Food, Drug and Cosmetic Act require pharmaceutical companies to prove drug efficacy, require firms to submit adverse reaction reports to the FDA, require drug advertising to include complete information about risks and benefits, and require informed consent from clinical study subjects.
• 1962: U.S. Army publicly issues AR 70-25, expanding regulation of human research beyond atomic, biological and chemical warfare, but not to “ethical medical and clinical investigations” that might benefit the subjects.
• 1963: American Medican Association forms Committee on Quackery, primarily to oppose chiropractic treatments.
• 1963: At the Willowbrook State School in Staten Island, New York, for children with mental retardation, physicians Saul Krugman and Robert W. McCollum infect children with hepatitis B to see if they can then be cured with gamma globulin.
• 1963: FDA requires investigators to certify proper informed consent. (21 CFR 130.3; moved to 45 CFR 46)
• 1963: Physician Chester M. Southam injects live cancer cells into 22 elderly patients at the Jewish Chronic Disease Hospital in Brooklyn, New York to see if their bodies would reject them; he is later elected vice president of the American Cancer Society.
• 1963: Stanley Milgram publishes controversial “Obedience to Authority” studies in which research subjects (“teachers”) punished slow-learning fake students with fake electric shocks. Deception of subjects violated principles of informed consent.
• 1964: American Association of University Professors and American Council on Education issues a statement on conflicts of interest in government-sponsored research.
• 1964: Drug Information Association (DIA) founded.
• 1964: World Medical Association’s “Declaration of Helsinki” requires informed consent. In contrast to the legal form of the Nuremburg Code, it takes the form of ethical guidelines.
• 1965: Henry Beecher, a professor at Harvard Medical School, delivers a lecture at Brook Lodge Conference Center describing published articles in scientific journals based on at least 50 ethically-questionable research protocols.
• 1966: FDA regulation 21 CFR 130.37 (later included in 45 CFR 46) defines elements and requirements of informed consent.
• 1966: Henry Beecher, a professor at Harvard Medical School, publishes “Ethics and Clinical Research” in the New England Journal of Medicine (NEJM). The article, detailing ethically-objectionable clinical trials, such as the transplantation of malignant melanoma tissue from a daughter to her mother, had been rejected by the Journal of the American Medical Association the previous year. Joseph Garland, Editor of the NEJM, negotiated Beecher down from at least 50 to just 22 examples.
• 1966: Laboratory Animal Welfare Act requires registration of animal research facilities and establishes rules for animal care.
• 1966: New York State Board of Regents censures and places on one year probation Drs. Chester M. Southam and Emmanual E. Mandel for an experiment involving the injection of live cancer cells into patients without informing them and, in some cases, against objections by their physicians.
• 1966: NIH creates Office of Protection from Research Risks (OPRR).
• 1966: NIH issues over $1 billion in research grants.
• 1966: Public Health Service (PHS), parent of NIH, issues “Policy Statement” requiring informed consent and the use of “committees of institutional associates” composed of professional and public members to review and approve PHS-funded research.
• 1966: William H. Stewart, Surgeon General of the U.S. Public Health Service, issues first U.S. government statement on the protection of human subjects, requiring prior review of clinical trials by the investigator’s institutional associates.
• 1967: FDA issues policy clarifying that informed consent must be in writing.
• 1967: Great Britain’s Royal College of Physicians publishes a report that questions the advisability of giving potential subjects a complete explanation of the experiment or even asking their consent.
• 1967: Heart Special Project Committee, an NIH external advisory group, recommends establishing a formal committee (i.e., data and safety monitoring board) to review accumulating data as a clinical trial progresses to monitor safety, effectiveness, and trial conduct issues.
• 1967: John Fletcher writes “”Human Experimentation: Ethics in the Consent Situation,”” discussing issues of informed consent (or lack thereof).
• 1967: NIH approves the practice of self-experimentation, under the condition that the safeguards should be the same as for any volunteer.
• 1968: Maurice Henry Pappworth, in Great Britain, writes “Human Guinea Pigs: Experimentation on Man,” arguing that medical researchers often take unnecessary risks with the health of subjects without the subjects’ knowledge.
• 1968: NIH opens John E. Fogerty International Center to coordinate international research.
• 1968: Radiation Control for Health and Safety Act gives FDA authority over devices that emit electronic radiation.
• 1969: The Hastings Center, a private bioethics research institute, is formed with lead funding of $25,000 per year from Eli Lilly & Company. (Lilly terminates its funding of the Center in 2000 when the Hastings Center Report publishes a special issue, “Prozac, Alienation, and the Self,” with articles critical of Prozac, a Lilly drug, and pharmaceutical company marketing practices.)
• 1970: In Upjohn v. Finch, the Court of Appeals upholds enforcement of the 1962 Kefauver-Harris Drug Amendments by ruling that commercial success alone does not constitute substantial evidence of drug safety and efficacy.
• 1971: FDA requires “institutional review committees” for clinical research under INDs.
• 1971: Georgetown University opens Kennedy Institute of Ethics, a university-based bioethics institute.
• 1972: American Hospital Association adopts “The Patient’s Bill of Rights.”
• 1972: Division of Biological Standards, with responsibility for regulating biologics, is transferred from NIH to FDA.
• 1972: National Institutes of Health forms Office for Protection from Research Risks to develop, implement and oversee compliance with Public Health Service “Policy on Humane Care and Use of Laboratory Animals.”
• 1972: Peter J. Buxton, a law student and former public health worker, exposes the Tuskegee Study of Untreated Syphilis in the Negro Male to Jean Heller, an Associated Press reporter, who publishes an expose’. Thousands of physicians had been aware of the study previously. The study is terminated the following year. (The study began in 1932. Penicillin was accepted for treatment of syphilis in 1943 and became widely available in 1951; it was withheld from the subjects. Between 1932 and 1974, 13 papers about the study were published in medical journals.)
• 1973: NIH sponsors multicenter kidney transplant histocompatibility study with two sites using electronic data capture (EDC) through teleprinter terminals connected via dial-up telephone lines to a mainframe computer.
• 1974: 45 CFR 46 Subpart B adds special protections for pregnant women and fetuses in clinical research.
• 1974: City of Philadelphia closes the clinical research program at Holmesburg Prison where, for 25 years, physician Albert M. Kligman conducted ethically-deficient experiments on prisoners under the auspices of the University of Pennsylvania.
• 1974: Family Educational Rights and Privacy Act protects student privacy.
• 1974: National Research Act requires institutional review boards for Department of Health, Education, and Welfare-funded biomedical and behavioral research involving human subjects, and calls for the formation of National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research, which issues the Belmont Report in 1978.
• 1974: Public Responsibility in Medicine and Research/Applied Research Ethics National Association (PRIM&R/ARENA) founded.
• 1975: A.H. Robins Co. recalls Dalkon Shield contraceptive device after four years on the market for causing severe pelvic infections.
• 1975-1978: National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research issues reports on research with fetuses (1975), prisoners (1976), children (1977), and persons institutionalized as mentally infirm (1978).
• 1975: World Medical Association’s Declaration of Tokyo expands on the Declaration of Helsinki with additional subject protections, including ethics boards with the authority to comment and provide guidance, but without the authority held by institutional review boards in the U.S. to approve or disapprove studies.
• 1976: Association of Clinical Research Professionals (ACRP) founded.
• 1976: California Medical Experimentation Act includes Experimental Subject’s Bill of Rights.
• 1976: Medical Device Amendments to Federal Food, Drug, and Cosmetic Act extend full FDA regulatory authority to medical devices, including the requirement for approval prior to marketing.
• 1977: FDA Bioresearch Monitoring Program is created to ensure quality and integrity of data, and safety, rights and welfare of human research subjects.
• 1977: FDA establishes Bioresearch Monitoring Program (BIMO).
• 1978: 45 CFR 46 Subpart C adds special protections for prisoners in clinical research.
• 1978: National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research issues Belmont Report, requiring respect for persons, beneficence and justice in clinical research.
• 1978: Society for Clinical Trials (SCT) is established.
• 1979: Institute of Clinical Research (ICR) founded in the UK.
• 1980: Controlled Clinical Trials, the journal of the Society for Clinical Trials, (later renamed Clinical Trials) publishes first issue.
• 1981: FDA issues regulations covering protection of human subjects, informed consent, and standards for institutional review boards.
• 1981: Title 45, Code of Federal Regulations, Part 46: Protection of Human Subjects establishes regulations for research supported by Department of Health and Human Services.
• 1982: Council for the International Organization of Medical Sciences (CIOMS) publishes “International Ethics Guidelines for Biomedical Research Involving Human Subjects,” including cross-cultural guidance for conducting research in developing countries.
• 1983: 45 CFR 46 Subpart D adds special protections for children in clinical research.
• 1983: Orphan Drug Act provides tax benefits and exclusive marketing rights to developers of drugs that treat rare diseases.
• 1984: Drug Price Competition and Patent Term Restoration Act (Hatch-Waxman Act) expands the categories of drugs, e.g., generics, eligible for Accelerated New Drug Applications (ANDAs) and adds up to five years of patent protection for drugs to offset the time required for FDA approval.
• 1985: Animal Welfare Act is amended to expand protections for animals used in research, including institutional animal care and use committees (IACUCs).
• 1985: FDA issues IND amendments clarifying requirements for clinical research with biological products, e.g., gene therapy.
• 1986: 1863 False Claims Act is amended to reward and protect whistleblowers, and otherwise strengthen the ability to impose civil liability for submitting a false or fraudulent claim for payment to the United States government, e.g., for double-billing a clinical trial sponsor and Medicare for clinical trial costs.
• 1986: Daniel Zagury, a French physician, tests an AIDS vaccine on himself.
• 1986: U.S. Representative Edward Markey issues report titled “American Nuclear Pigs: Three Decades of Radiation Experiments on U.S. Citizens,” describing numerous government experiments that intentionally released radioactive materials into the environment in the 1940s through 1970s.
• 1987: Canadian bioethicist Benjamin Freedman defines the concept of clinical equipoise in a New England Journal of Medicine article.
• 1987: FDA issues 21 CFR 312.34 regulations for Treatment INDs, allowing use of investigational new drugs showing promise in clinical testing for treating serious or immediately life-threatening conditions.
• 1987: FDA issues 21 CFR 312.106 regulations permitting new drug applications to be based solely on data from overseas clinical trials.
• 1987: Saul Shiffman creates first handheld electronic subject diary to capture data in a trial of addictive behaviors.
• 1988: French government enacts “la Loi Huriet” (the Huriet Law) to protect healthy human research subjects.
• 1989: “Stark I” law, part of the Omnibus Budget Reconciliation Act of 1989, prohibits physician referral of Medicare patients to clinical laboratories in which the physician or member of his/her family has a financial relationship.
• 1990: Professor Gordon Guyatt uses the term “evidence-based medicine” in a document for applicants to the Internal Medicine residency program at McMaster University in Hamilton, Ontario.
• 1990: Regulatory authorities in U.S., E.U. and Japan create International Conference on Harmonisation (ICH).
• 1990: Safe Medical Devices Act requires medical device tracing, registries and post-marketing surveillance.
• 1991: David Sackett, founder of Canada’s first department of clinical epidemiology at McMaster University in 1967, uses the term “evidence-based medicine” in the book, “Clinical Epidemiology.”
• 1991: Department of Health & Human Services and 15 other government departments and agencies (not including FDA) adopt the “Common Rule” (45 CFR 46) governing conduct of clinical research. FDA regulations 21 CFR 50 and 21 CFR 56 are somewhat different.
• 1991: Federal Patient Self-Determination Act (PSDA) requires Medicare-funded healthcare facilities to comply with state informed consent laws.
• 1992: FDA bans silicone breast implants.
• 1992: FDA issues regulations for accelerated approval and a “parallel-track” mechanism so that patients with AIDS, whose condition prevents them from participating in controlled clinical trials, can receive investigational drugs shown in preliminary studies to be potentially useful.
• 1992: Generic Drug Enforcement Act imposes debarment and other penalties for criminal convictions related to NDAs for generic and branded drugs.
• 1992: Prescription Drug User Fee Act requires pharmaceutical companies to pay fees on certain NDAs and supplements, establishments and products, to fund 700 additional FDA staff.
• 1993: “Stark II” law, part of the Omnibus Budget Reconciliation Act of 1993, expands Stark I’s laboratory referral prohibition to include a number of “designated health services” and Medicaid services, including physical and occupational therapy; radiology; durable medical equipment, parenteral/enteral and prosthetic items; home health services; outpatient prescription drugs and hospital services.
• 1993: Albuquerque Tribune reveals that government-sponsored researchers injected plutonium into unknowing subjects to study the effects of the atomic bomb.
• 1993: Cochrane Collaboration is founded under the leadership of British physician Iain Chalmers, to publish systematic reviews and meta-analysis articles in support of evidence-based medicine.
• 1993: FDA establishes MedWatch safety information and adverse event reporting program.
• 1993: ICMJE approves statement on conflict of interest in peer review and publication.
• 1993: In the movie (unlike the television series), The Fugitive, Dr. Richard Kimble (Harrison Ford) is framed for the murder of his wife because of his intention to expose negative clinical trial results.
• 1993: National Academy of Sciences publishes report estimating that over 60,000 servicemen were used in chemical research during World War II.
• 1993: National Institutes of Health Revitalization Act mandates inclusion of women and minorities in federally-funded, population-based studies.
• 1994: Advisory Committee on Human Radiation Experiments is created, leading to formation of National Bioethics Advisory Commission in 1995.
• 1994: Dietary Supplement and Health Education Act exempts dietary supplements and herbal remedies from FDA oversight.
• 1995: Based on findings of the Advisory Committee on Human Radiation Experiments, which was formed in 1994 due to articles published by Eileen Welsome in the Albuquerque Tribune in 1993, National Bioethics Advisory Commission is created to advise the President on bioethics issues.
• 1995: Medicare agrees to cover costs related to clinical trials involving marketed medical devices under investigational device exemptions.
• 1995: On behalf of the American people, President Bill Clinton apologizes to survivors of human radiation experiments conducted by U.S. government.
• 1996: FDA regulation 21 CFR 50.24 allows exceptions from informed consent in emergency research.
• 1996: International Conference on Harmonisation (ICH) publishes E6(R1): Good Clinical Practice: Consolidated Guideline (with editorial corrections of initial version earlier that year).
• 1997: FDA establishes Adverse Event Reporting System (AERS) database for safety surveillance.
• 1997: FDA Modernization Act offers marketing incentives for pediatric studies, implements risk-based regulation of medical devices, authorizes a public registry of clinical trials (www.clinicaltrials.gov), and expands access to investigational therapies and diagnostics.
• 1997: On behalf of the American people, President Bill Clinton apologizes to surviving Tuskegee experimental subjects.
• 1997: Security and Exchange Commission (SEC) brings an insider-trading case against Milton Mutchnick, MD, a gastroenterologist at Wayne State University who was the lead investigator for a clinical trial that showed negative results for an antihepatitis drug developed by Alpha 1 Biomedicals Inc. and licensed to Sciclone Pharmaceuticals Inc. Dr. Mutchnick pays a civil penalty of $163,494 without admitting or denying the charges.
• 1998: FDA requires efficacy and safety data by demographic subgroup (e.g., gender, race and age) in new drug applications, as well as enrollment data for demographic subgroups, in annual IND reports.
• 1998: FDA requires financial disclosure by clinical investigators.
• 1998: Protection of Pupil Rights Amendment protects student privacy in surveys.
• 1999: Jesse Gelsinger dies in gene transfer experiment that would not have benefited his health.
• 1999: United Healthcare, a large managed care organization, agrees to pay its subscribers’ costs associated with participating in cancer clinical trials.
• 2000: Department of Health and Human Services transfers Office for Protection from Research Risks from National Institutes of Health to Office of the Secretary, and renames it the Office for Human Research Protections
• 2000: National Coverage Decision provides for Medicare coverage of “routine” costs of “qualifying” clinical trials.
• 2000: World Health Organization (WHO) issues “Operational Guidelines for Ethics Committees That Review Biomedical Research.”

Giorni nostri:

• 2000: World Medical Association, in a meeting in Edinburgh, expands on the Declarations of Helsinki and Tokyo by prohibiting the use of placebo controls when there is a known effective treatment. Subsequent clarification removes the prohibition.
• 2001: After Ellen Roche dies during an asthma drug study, Office for Human Research Protections suspends all Federally-funded clinical research at Johns Hopkins University School of Medicine and affiliated institutions. At the time, Johns Hopkins University was the leading recipient of Federal research funding.
• 2001: Association for the Accreditation of Human Research Protections Programs (AAHRPP) is established.
• 2001: Clinical Trials Directive (European Union Directive 2001/20/EC) simplifies and harmonizes (“approximates”) administrative provisions governing clinical trials in the European Union.
• 2001: Health Insurance Portability and Accountability Act requires privacy and security for personal health information.
• 2001: In the cases of Ericka Grimes and Myron Higgins v. Kennedy Krieger Institute, relating to a research study on the prevention of lead poisoning among inner-city children, Maryland Court of Appeals rules that parents cannot consent to participation by their children “in nontherapeutic research or studies in which there is any risk of injury or damage to the health of the subject.”
• 2002: Animal Efficacy Rule authorizes FDA to approve drugs based on animal test results if human testing is not practical because the drugs prevent or ameliorate “serious or life-threatening conditions caused by exposure to lethal or permanently disabling toxic biological, chemical, radiological, or nuclear substances.”
• 2002: Best Pharmaceuticals for Children Act provides six-month patent extension for manufacturers who conduct pediatric trials.
• 2002: Medical Device User Fee and Modernization Act authorizes user fees for FDA premarket reviews.
• 2002: Pharmaceutical Research and Manufacturers Association (PhRMA) adopts “Principles on Conduct of Clinical Trials.”
• 2002: Time Magazine (April 22) publishes cover story by Michael D. Lemonick and Andrew Goldstein, titled, “Human Guinea Pigs: Some patients join clinical trials out of desperation. Others to help medicine advance. Whom do you blame if they get sick – or even die?”
• 2003: American Association for Cancer Research removes the name of Cornelius P. Rhoads from its annual award given to young cancer investigators, because it came to its notice that at least 13 Puerto Rican subjects had died in the 1930s after Dr. Rhoads injected them with cancer cells. Dr. Rhoades also made highly racist remarks about the inhabitants of Puerto Rico.
• 2003: FDA approves Bristol-Myers Squibb’s Pravigard PAC (pravastatin sodium and buffered aspirin) based on Bayesian data analysis.
• 2003: In Diaz v. Hillsborough County Hospital Authority lawsuit, class action plaintiffs settles case for $3.8 million in damages for “dignitary harm” that involves no physical harm.
• 2003: National Coverage Decision states that Medicare/Medicaid will cover certain costs associated with device trials.
• 2003: Pediatric Research Equity Act gives FDA authority to require pediatric studies of pharmaceutical products.
• 2003: Pfizer uses Bayesian methods to discontinue the adaptive ASTIN trial of treating stroke with neutrophil inhibitory factor (NIF), based on futility.
• 2003: Wolfgang Weyers writes “The Abuse of Man: An Illustrated History of Dubious Medical Experimentation,” a comprehensive history of clinical research.
• 2004: Bristol-Myers Squibb’s Prove-It study demonstrates that Pfizer’s Lipitor is safer than Bristol-Myers Squibb’s Pravachol.
• 2004: FDA initiates Critical Path Initiative to transform the way FDA-regulated products are developed, evaluated, manufactured and used.
• 2004: Pharmaceutical Research and Manufacturers Association (PhRMA) updates its clinical research principles to include timely communication of clinical trial results, whether those results are positive or negative.
• 2005: International Committee of Medical Journal Editors (ICMJE) requires registration of clinical trials prior to publication.
• 2005: In the movie, The Constant Gardener, Justin Quayle (Ralph Fiennes) discovers unethical testing of drugs on impoverished Africans.
• 2005: Journal of Clinical Research Best Practices publishes first issue.
• 2005: World Health Organization (WHO) specifies “Minimal Registration Data Set” for registering clinical trials.
• 2007: Food and Drug Administration Amendments Act (FDAAA) expands registry requirement to all clinical trials (except Phase I), gives FDA enforcement power over post-marketing commitment studies, and allows FDA to require a Risk Evaluation and Mitigation Strategy (REMS) for drugs associated with greater safety risks.
• 2008: FDA’s Office of Critical Path Programs announces the Clinical Trials Transformation Initiative (CTTI), a public-private partnership to improve the quality and efficiency of clinical trials.
• 2010: Congress enacts Patient Protection Affordable Care Act, including the Physician Payment Sunshine Provision, which requires, among other things, that clinical investigators disclose financial compensation in excess of $10 from pharmaceutical and medical device companies.
• 2011: President’s Bioethics Commission for the Study of Bioethical Issues publishes report, “‘ETHICALLY IMPOSSIBLE’ STD Research in Guatemala
  from 1946 to 1948,” on its investigation of U.S. Public Health Service clinical research.