Clinical research milestones

Vol. 2, No. 6, June 2006 “Can You Handle the Truth?”

Milestones in Clinical Research
By Norman M. Goldfarb

Clinical research and its regulatory environment have evolved step-by-step over many
years. Since Walter Reed administered written consent forms in a yellow fever transmission
study in 1900, the pace of change has accelerated dramatically.
Table 1 includes over 200 milestones that mark sometimes erratic, but generally forward
progress. In many cases, the milestones are the first of their kind, but this article generally
does not make that claim. The sources in the bibliography tell parts of the story in much
more detail, and what a fascinating story it is.
This article will be updated as new information becomes available. For example, the
following events have not been identified:
• First clinical trial managed by a contract research organization (CRO)
• First independent (central) IRB
• First Data and Safety Monitoring Board (DSMB)
• First clinical trial with a recombinant DNA product
• First gene therapy clinical trial
• First adaptive clinical trial
There are, no doubt, other milestones that must endure the ignominy of exclusion until their
existence is called the author’s attention. For example, Table 1 is highly U.S.-centric.
Although the author has attempted to verify the information in Table 1, there may be
factual errors that cry out for correction.
Unless stated otherwise, the milestones occurred in the United States.

Table 1. Milestones

~600 Daniel designs and participates in a controlled nutritional study in the court of
BCE Nebuchadnezzar II, King of Babylon. Study is reported in the Old Testament
sometime later.
~400 Hippocratic Oath defines responsibilities of physicians to their patients (with no
BCE mention of experimentation). Hippocrates, who lived in Greece probably
sometime between 460 and 380 BCE, probably did not write the oath.
400- Charaka Samhita, a textbook in verse of Ayurvedic medicine, is written in
200 India.
BCE
~200 Sushruta Samhita, a textbook in verse of Ayurvedic surgery, is written in India.
137 Attalus III (Philometer), King of Pergamum, tests the effects of extracts from
BCE poisonous plants by offering them in beverages to his guests.
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

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© 2006 Norman M. Goldfarb

times to examine the development of the fetuses. The investigators reported
that boys developed in 40 days and girls took 80 days.
~1030 Avicenna (AbF ‘AlH al-Husayn ibn ‘Abd AllIh ibn SHnI), 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.
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 his treatments vs. that of other
physicians with 200 to 500 fever and pleurisy patients, backed by a wager of
300 florins that is not accepted.
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.
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.
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.
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.
1799 John Haygarth conducts placebo-controlled and single-blinded (with sham
wooden “medical devices”) studies of the use of iron and brass rods to relieve
pain.
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.
1820 Eleven physicians create the U.S. Pharmacopeia, which includes
recommendations of the best drugs for treating diseases.

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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.
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.
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.”
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).
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.
1871 Court rules in Carpenter v. Blake that the physician must fully inform the
patient before departing from standard medical practice.
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.
1883 Caroline Earl White founds the American Anti-Vivisection Society to protect
animals from experimentation.
1884 Possibly after successful experiments with dogs, Louis Pasteur first tests an
antidote to rabies on an infected child, 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.
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.
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 William Henry Welch begins publication of the Journal of Experimental
Medicine.
1898 American Journal of Physiology begins publication.
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 “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 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.
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.
1901 USDA Division of Chemistry is promoted to Bureau of Chemistry, with a new
emphasis on drugs.
1902 Hygienic Laboratory launches three formal research programs under the
direction of Ph.D.s.


1902 USDA Bureau of Chemistry creates Drug Laboratory.
1902 After 13 children die from diphtheria antitoxin contaminated with tetanus
spores, 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.
1903 Italian civil authorities reprimand a physician for successfully infecting a man
with malaria through inoculation.
1905 American Medical Association establishes Council on Pharmacy and Chemistry
to set standards for drug manufacturing and advertising, and fight against
quack patent medicines.
1906 “The Jungle,” by Upton Sinclair, publicizes lack of purity in meat products,
leading to passage of the Pure Food and Drug Act.
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.
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.”
1907 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.
1912 U.S. Supreme Court rules in "Dr. Johnson's Mild Combination Treatment for
Cancer” case that Pure Food and Drug Act does not prevent drug companies
from making false claims for their products.
1912 Shirley Amendment makes false drug claims illegal.
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.
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.
1923 R.A. Fisher and W.A. MacKenzie perform statistical randomization in an
agricultural experiment.
1923 The “Friends of Medical Progress,” later renamed the “American Association for
Medical Progress,” is founded in Boston to support medical 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 Ransdell Act renames Hygienic laboratory the National Institute of Health (NIH)
and expands its functions.
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.
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.
1931 After a local pediatrician prepares and administers a faulty tuberculosis vaccine
that kills 75 children in Lubeck, German government enacts “Regulation on
New Therapy and Experimentation”, requiring human experiments to be
preceded by animal experiments.
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 UK Medical Research Council creates Special Committee on Clinical Trials.
1933 German Law on Animal Protection requires government approval for
experiments that may cause appreciable pain or damage to animals.
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 recommends randomization by alternately assigning
subjects in clinical trials in “Principles of Medical Statistics.”
1938 Sales of Elixir Sulfanilamide are stopped after a poisonous ingredient kills 107
people, mostly children. Scandal leads to passage of the Food, Drug, and
Cosmetic Act.
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.
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 on
Medical Research to fund and coordinate research on military medical
problems.
1944 Biologic Control Act is amended to require biological product – not just
establishment – licensing.
1944 Public Health Service Act authorizes NIH to conduct clinical research.
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.
1946 American Medical Association adopts code of ethics for research on human
subjects.
1946 Bradford A. Hill recommends the use of fully randomizing subjects in clinical
trials.
1946 British Medical Research Council begins placebo-controlled, randomized clinical
trial of whooping-cough vaccination, published in 1951.
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 World Medical Association updates and clarifies Hippocratic Oath in Declaration
of Geneva.
1948 United Nations General Assembly adopts Universal Declaration of Human
Rights, including the right to “security of person.”
1948 Philip D'Arcy Hart and Marc Daniels publish paper on a placebo-controlled,
randomized clinical trial for tuberculosis treatment with streptomycin, in the
British Medical Journal.
1948 Andrew Ivy publishes “The History and Ethics of the Use of Human Subjects in
Medical Experiments.”
1949 World Medical Association adopts “International Code of Medical Ethics,” stating
that “a doctor owes to his patient complete loyalty.”
1951 Durham-Humphrey Amendment requires that drugs unsafe for self-medication
be labeled for sale by prescription only.
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- Department of Defense exposes over 200,000 enlisted men to radiation during
1962 atmospheric tests of atomic bombs in Nevada.
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.
1953 NIH opens Warren Grant Magnuson Clinical Center hospital for intramural
research, with Medical Board 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).
1950s Double-blind experimental design becomes popular for drug studies.
1955 National Cancer Institute conducts randomized cancer trial on acute leukemia
and solid tumors.
1955 C. Gordon Zubrod leads the creation of cancer cooperative groups, supported
by the Cancer Chemotherapy National Service Center (CCNSC) at NIH.
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.
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 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.
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 FDA initiates Drug Efficacy Study Implementation (DESI) program to review
effectiveness of drugs marketed prior to 1962.
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 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.
1964 Drug Information Association (DIA) founded.
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 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 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 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 Laboratory Animal Welfare Act requires registration of animal research facilities
and establishes rules for animal care.
1966 NIH issues over $1 billion in research grants.
1967 John Fletcher writes "Human Experimentation: Ethics in the Consent Situation,"
discussing issues of informed consent (or lack thereof).
1968 Radiation Control for Health and Safety Act gives FDA authority over devices
that emit electronic radiation.
1968 Maurice Henry Pappworth 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.
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.)
1971 Georgetown University opens Kennedy Institute of Ethics, a university-based
bioethics institute.
1971 FDA requires “institutional review committees” for clinical research under INDs.
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.)
1972 American Hospital Association adopts “The Patient's Bill of Rights.”
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 Division of Biological Standards, with responsibility for regulating biologics, is
transferred from NIH to FDA.
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 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 45 CFR 46 Subpart B adds special protections for pregnant women and fetuses
in clinical research.
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 Family Educational Rights and Privacy Act protects student privacy.
1974 Public Responsibility in Medicine and Research/Applied Research Ethics National
Association (PRIM&R/ARENA) founded.
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.
1975 A.H. Robins Co. recalls Dalkon Shield contraceptive device after four years on
the market for causing severe pelvic infections.
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.
1976 California Medical Experimentation Act includes Experimental Subject’s Bill of
Rights.
1976 Association of Clinical Research Professionals (ACRP) founded.
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.
1977 FDA Bioresearch Monitoring Program is created to ensure quality and integrity
of data, and safety, rights and welfare of human research subjects.
1978 45 CFR 46 Subpart C adds special protections for prisoners 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, later renamed Contemporary 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 Orphan Drug Act provides tax benefits and exclusive marketing rights to
developers of drugs that treat rare diseases.
1983 45 CFR 46 Subpart D adds special protections for children in clinical research.
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 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 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 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.
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 Safe Medical Devices Act requires medical device tracing, registries and post-
marketing surveillance.
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.
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.
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 FDA bans silicone breast implants.
1993 Albuquerque Tribune reveals that government-sponsored researchers injected
plutonium into unknowing subjects to study the effects of the atomic bomb.
1993 National Academy of Sciences publishes report estimating that over 60,000
servicemen were used in chemical research during World War II.
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 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 Medicare agrees to cover costs related to clinical trials involving marketed
medical devices under investigational device exemptions.
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 On behalf of the American people, President Bill Clinton apologizes to survivors
of human radiation experiments conducted by U.S. government.
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.
1998 FDA requires financial disclosure by clinical investigators.
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 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.
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.
2000 National Coverage Decision provides for Medicare coverage of “routine” costs of
“qualifying” clinical trials.
2001 Health Insurance Portability and Accountability Act requires privacy and
security for personal health information.
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
2001 Clinical Trials Directive (European Union Directive 2001/20/EC) simplifies and
harmonizes (“approximates”) administrative provisions governing clinical trials
in the European Union.
2001 Association for the Accreditation of Human Research Protections Programs
(AAHRPP) is established.
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 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 Medical Device User Fee and Modernization Act authorizes user fees for FDA
premarket reviews.
2002 Best Pharmaceuticals for Children Act provides six-month patent extension for
manufacturers who conduct pediatric trials.
2002 Pharmaceutical Research and Manufacturers Association (PhRMA) adopts
“Principles on Conduct of Clinical Trials.”
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.”
2003 Pediatric Research Equity Act gives FDA authority to require pediatric studies of
pharmaceutical products.
2003 National Coverage Decision states that Medicare/Medicaid will cover certain
costs associated with device trials.
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 Wolfgang Weyers writes “The Abuse of Man: An Illustrated History of Dubious
Medical Experimentation,” a comprehensive history of clinical research.
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.


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 World Health Organization (WHO) specifies “Minimal Registration Data Set” for
registering clinical trials.
2005 Journal of Clinical Research Best Practices publishes first issue.

Acknowledgments
The author gratefully acknowledges the contributions of Robert J. Levine and Susan Lederer
to this article.

Bibliography
1. “A Short History of the National Institutes of Health”, Victoria A. Harden, last accessed
on 5/9/06 at http://history.nih.gov/exhibits/history/index.html
2. “Biologics Development: A regulatory Overview, Third Edition”, Mark Mathieu, editor,
2004
3. “Foundations of Clinical Research: Applications to Practice, Second Edition”, Leslie Gross
Portnoy and Mary P. Watkins, 2000
4. “Powerful Medicines”, Jerry Avorn, 2004
5. “Protecting America’s Health: The FDA, Business and One Hundred Years of Regulation”,
Philip J. Hilts, 2003
6. “Subjected to Science: Human Experimentation in America before the Second World
War”, Susan E. Lederer, 1995
7. “The Abuse of Man: An Illustrated History of Dubious Medical Experimentation”,
Wolfgang Weyers, 2003
8. “The Progress of Experiment: Science and Therapeutic Reform in the United States,
1900-1990”, Harry J. Marks, 1997
9. “Undue Risk: Secret State Experiments on Humans”, Jonathan D. Moreno, 2001

Author
Norman M. Goldfarb is Managing Director of First Clinical Research LLC, a provider of clinical
research best practices information, consulting and training services. Contact him at
1.650.465.0119 or ngoldfarb@firstclinical.com.
V2 July 1, 2006


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