Introduction
For many years, medical research had gone on largely
unregulated despite the fact that philosophers had been
discussing the need to
protect the safety and welfare of the human research
subject volunteers. In ancient Egypt, the first
century physician Celsius justified experiments on
condemned criminals using words which became the classic
defense for hazardous experimentation: "It is not cruel
to inflict on a few criminals sufferings which may
benefit multitudes of innocent people through all
centuries." Brady,
Joseph V. and Jonsen, Albert R. "The Evolution of
Regulatory Influences on Research with Human Subjects."
A Handbook for Institutional Review Boards. Ed.
Greenwald, Robert A. et. al. New York: Plenum Press,
1982. 3-18.
Today, people who are volunteering in research projects
are
safer than ever before. There are tremendous efforts
by multiple groups to
protect the safety and welfare of those who are good
enough to stand up and decide to go first and try a new
treatment. Especially, over the years, as tragedies have
occurred, legislation to prevent their reoccurrence
ensued. In the early 1900s in America, medicine and
pharmacology was made up of folklore, charlatans, and
alternative medicine. Numerous accounts of "snake oil
salesmen" abounded.
In 1820, eleven physicians met in Washington, D.C., to
establish the US Pharmacopeia, the
first compendium of standard drugs for the United
States.
In 1848, the Drug Importation Act passed by Congress
requires US Customs Service inspection to stop entry of
adulterated drugs from overseas.
In 1862,
President Lincoln appoints a chemist, Charles M.
Wetherill, to serve in the new Department of
Agriculture. This was the beginning of the Bureau of
Chemistry, the predecessor of the Food and Drug
Administration.
The 1870s saw the rise of the
Patent Medicine Industry. Because there were
no restrictions on advertising, labeling or contents of
any products, the patent medicine industry made up all
sorts of concoctions, including the opiates, cocaine and
other drugs, and sold them with the most extravagant
advertising claims.
In 1880,
Peter Collier, Chief Chemist, US Department of
Agriculture, recommends passage of a national
food and drug law, following his own food adulteration
investigations. The bill was defeated, but during the
next 25 years, more than 100 food and drug bills were
introduced in Congress.
In 1883, Dr. Harvey W. Wiley becomes chief chemist,
expanding the Bureau of Chemistry's food adulteration
studies. Campainging for a federal law, Dr. Wiley is
called the "Crusading Chemist" and "Father of the Pure
Food and Drugs Act." He retired from government service
in 1912 and died in 1930.
In 1897, the Tea
Importation Act passed, providing for Customs
inspection of all tea entering US ports, at the expense
of the importers.
In 1898, the Association of Official Agricultural
Chemists (now called AOAC International) establishes a
Committee on Food
Standards headed by Dr. Wiley. States begin
incorporating these standards into their food statutes.
In 1902, the Biologics Control Act was passed to ensure
purity and safety of serums, vaccines, and similar
products used to prevent or treat diseases in humans.
On June 30, 1906, the
Pure Food and Drug Act was first enacted. It
created the FDA in Washington. It said certain drugs
could only be sold on prescription. And labeled
habit-forming drugs. This was the beginning of the
modern day FDA.
This law came about as a result of an exposé written
by Upton Sinclair entitled The Jungle. In it he
exposed the horrible sanitary conditions that were part
and parcel of the meat packing industry in that era. The
result was the passage of the 1906 food and drug law
that legislated that drugs must be proved and tested to
be "pure" prior to their being available for sale to the
public at large. Prior to this, there were ridiculous
claims that these "patent medicines," as they were
called because their secret ingredients were patented,
could cure everything. In retrospect, the majority of
these medicines only contained alcohol. Also that same
day, the Meat Inspection Act was passed in
reaction to shocking disclosures on unsanitary
conditions in meat-packing plants in Chicago, as
outlined in Upton Sinclair's exposé The Jungle.
1907 saw the first
Certified Color Regulations that listed the
seven colors found suitable for use in foods.
In 1911, US vs. Johnson was a Supreme Court ruling
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.
In 1912, Congress enacts the
Sherley Amendment to overcome the ruling in
US vs. Johnson. It prohibits labeling medicines
with false therapeutic claims intended to defraud the
purchaser, a standard difficult to prove.
In 1913, the
required that food package contents
be "plainly and conspicuously marked on the outside of
the package in terms of weight, measure of numerical
count."
In the 1914 case US vs. Lexington Mill and Elevator
Company, the Supreme Court issued its first ruling
on food additives. Also, the
Harrison Narcotic Act passed, requiring
prescriptions for products exceeding the allowable limit
of narcotics and mandated increased record keeping for
physicians and pharmacists who dispense narcotics.
In the 1924 case
US vs.
95 Barrels Alleged Apple Cider Vinegar, the
Supreme Court ruled that the Food and Drugs Act condemns
every statement, design or device on a product's label
that may mislead or deceive, even if technically true.
In 1930, the name of the Food, Drug and Insecticide
Administration is shortened to the
Food and Drug Administration (FDA) under an
agricultural appropriations act.
In 1933, the FDA recommended a complete revision of the
obsolete 1906 Food and Drugs Act. The first bill is
introduced into the Senate, launching a five-year
legislative battle.
In 1938, the Food, Drug and Cosmetic Act was passed. Its
main tenet was that drugs now needed to be proven
"safe!" That is, before 1938, the law only mandated that
drugs were pure. There was no thinking that we should
test them first to make sure that they were safe. In
1937, the Massengill Drug Company would have their name
etched into the history of things gone wrong with drugs.
At the time they were working on trying to formulate a
liquid formulation of their popular antibiotic,
sulfanilamide. It was thought that with the coming flu
season if they could make an elixir of sulfanilamide
that this would be a big seller to the pediatricians.
Well, without any thought whether or not this new
formulation was safe, Massengill released their new
wonder drug to the children with flu in 1937.
Unfortunately, they used ethylene glycol (antifreeze) to
make the sufla water-soluble. At the time medical
science didn't know that ethylene glycol was toxic to
the kidneys. The children abruptly went to acute renal
failure. Since hemodialysis was not invented as of yet,
107 of them died! It was
in reaction to this horrific tragedy that the
1938 Food, Drug and Cosmetic Act ensuring that our
drugs are safe was enacted. Human Radiation
Experiments Between
1944 and 1974, the government sponsored several thousand
human radiation experiments. They involved exposing
people to radioactive tracers in doses likely to cause
physical harm. During this time there was little
attention paid to issues of fairness in the selection of
the participants. Research was conducted without their
awareness or consent and on participants not likely to
derive any directly medical benefit. These research
errors were finally exposed in 1993! And in 1994,
President Clinton created the Advisory Committee on
Human Radiation Experiments to identify ethical and
scientific standards for evaluating these events, and to
make recommendations to ensure that past wrongdoings
cannot be repeated.
In 1951, the Durham-Humphrey Amendment defined
prescription drugs as those that must be taken under a
doctor's supervision.
In 1962, the
Kefauver-Harris Amendments to the Food, Drug and
Cosmetic Act were passed ensuring that our drugs were
now required to be proven
"effacious!" That is, finally, prior to a
drug making it all the way to the marketplace, drug
studies were required to be performed showing that this
brand new treatment actually
works! This amendment also came
retrospectively as the result of a deficiency in our
system to ensure only good new investigational
treatments make it to our drug store shelves. In 1961,
there was research on a investigational new drug to
treat morning sickness and insomnia in pregnant women
called thalidomide. At the time, doctors that
were principal investigators in research studies were
not required to keep the investigational study drug in a
secure locked environment with limited access as we do
today. In addition, nobody thought at the time that it
was wrong to give out free samples of an
investigational study drug to patients not enrolled in a
formal research study. During the early 1960s, the world
started to see children being born with a horrific birth
defect called phocomelia. Over 300 infants were born
with missing extremities. Some of them had both arms and
legs missing! The United States government was shocked
by this horrible tragedy that occured. In an attempt to
make sure history didn't repeat itself again, the
Kefauver-Harris Amendment was enacted, ensuring that all
investigational study drugs now had to be strictly
limited to sole use by participants who have agreed to
become research volunteers in an investigational new
drug study.
Alternative Medicines Still
no law guaranteeing the three basic qualities of a
good drug: Pure, Safe, and Efficacious. The
Nuremberg Code
The international military tribunal in Nuremberg,
Germany, in 1947, tried 26 German physicians for war
crimes against humanity for recruiting unwilling
prisoners for horrific, fatal medical experiments. The
Nuremberg Code was a result of this. It attempts to make
sure history doesn't repeat itself ever again. The Code
outlines the fundamental ethical principles in human
subject research and is regarded as the first
internationally recognized set of guidelines to help
promote safety. Its most important principle is: "The
voluntary consent of the human research subject is
absolutely essential." It also states that the risks to
the volunteers should not outweigh the humanitarian
importance of the problem. Other tenets include: only
doing research if there is no other means of obtaining
this information, and it will be to the good of society;
we should do preliminary tests on animals; we should
avoid all unnecessary physical and mental suffering and
injury; no experiments where there is an a priori
reason to believe that death or disabling injury will
occur; physicians shouldn't enroll themselves as
subjects like Dr. Jeckyl and Mr. Hyde; the degree of
risk shouldn't supersede the potential benefit; proper
preparations should be made to protect against even
remote possibilities of injury; experiments should only
be conducted by scientifically qualified persons; the
subject has the right to leave the experiment at any
time for any reason without prejudice; and the scientist
should terminate the study should he become aware that a
much better treatment has become available. NIH Policy on the
Protection of Human Research Subject Volunteers
Back in 1953, the NIH produced the first official US
federal policy for the protection of human participants.
This policy provided a mechanism for prospective review
of research by individuals who had no direct involvement
or intellectual investment in the research. This
heralded the beginning of the first IRB. The Wichita Jury Case
In 1953, University of Chicago researchers
tape-recorded the deliberation of juries in six civil
cases, with the consent of the judge and counsel for
both sides, but without the jurors' knowledge. The
researchers were investigating whether the comments of
some lawyers might have inappropriately affected the
deliberative process. When word of the research leaked
out (one of the tapes was played at a Bar Association
conference), public outrage led to Senate hearings
chaired by James O. Eastland. Even though there was no
evidence that the recording had influenced the actions
of the jury, it was felt that the possibility of further
recordings being made might affect jurors' statements or
deliberations. A federal law was passed in 1956
banning all recording of jury proceedings. Timothy
Leary and Richard Alpert
In the 1960s, these two Harvard faculty (Leary was
lecturer in Social Relations and Alpert was assistant
professor at the Ed School) worked together at the
Center for Research in Personality. Hallucinogenic drugs
were not then illegal and they experimented with
psilocybin and LSD obtained from Sandoz Pharmaceuticals,
which were also dispensed to friends, associates and
students. As time passed, the research became more and
more freewheeling and, in the opinion of many
departmental colleagues, rapidly lost any semblance of
academic rigor. At this time the University Health
Services was just formulating its policies regarding the
use of human research subject volunteers. An agreement
was reached with Alpert and Leary in the fall of 1961
that they would not include any undergraduates in their
research. In early 1962, the two separated their
activities from the Center for Research in Personality
and formed their own private organization, the
International Federation for Internal Freedom (IFIF).
Eventually, both were fired from the university, Alpert
for having given psilocybin to an undergraduate in 1962
in violation of the UHS agreement, and Leary for failing
to teach his scheduled classes in the spring of 1963. Research on Obedience to Authority
At Yale University in the early 1960s, Stanley Milgram
was a social psychologist who devised a series of
experiments to examine the circumstances under which
naïve individuals would follow instructions whose
consequence was the apparent injury of another person.
Publication of the research, and a dramatic film of the
study, generated much controversy among psychologists.
Some argued that subjects had been harmed, if not
through the stress of the experiment itself, then
through the "inflicted insight" into their own
personalities. Nevertheless, the relevance of the
research to what was current events of the day, the
trial of Adolph Eichman, who maintained that he was just
following orders as he signed papers condemning
concentration camp victims to death, made the findings
all the more compelling. The Jewish
Chronic Disease Hospital Study
In 1963, studies were undertaken in Brooklyn, NY, at
the Jewish Chronic Disease Hospital, which is now called
Interfaith Hospital of Brooklyn. The doctors then did a
terrible "study" on unwitting, unsuspecting,
unconsenting patients on the body's ability to reject
cancer cells. They injected live cancer cells
intravenously into patients and watched to see if they
developed any signs of neoplasia. They then proudly
published their results for the world to read. The Willowbrook Study
In the early 1960s, unethical research was conducted at
the Willowbrook State School in Staten Island, NY, on
vulnerable mentally retarded children to better
understand the natural history of the hepatitis virus.
Most of the kids "caught" the highly infectious virus
after they came there. The doctors then decided to
"coerce" the parents into enrolling their children in an
experimental study whereby their children were
deliberately infected with the live hepatitis virus.
Only parents who agreed to the research were able to get
their retarded children into Willowbrook! This
controversial case raised important questions about the
adequacy and freedom of consent, inadequate disclosure
of the child's risk of later developing chronic liver
disease, and the lack of information given to parents
about access of doses of gamma-globulin.
The Declaration of Helsinki
First adopted by the World Medical Association in 1964
and subsequently modified
every couple of years, it is a landmark international
agreement on making additional safety recommendations to
the Nuremberg Code. It said we should do preliminary
experiments on animals prior to recruiting humans. It
pointed out that we shouldn't enroll a human in a study
unless the importance is in proportion to the risk. It
also recommended formation of safety committees that
later on became data safety monitoring boards (DSMB) and
Institutional Review Boards (IRB). The Public Health Service
In 1966, the Public Health Service was created. This
led the way to providing research volunteers with
informed consent with the use of informed consent
forms (ICF) to make sure that they adequately understand
the risks, benefits and alternative treatments of the
proposed medical care they will receive in the research
study and that they voluntarily agree with the proposed
investigational treatment plan without any element of
coercion. In addition, it led to the formation of
Institutional Review Boards (IRB) whose function
would be one of oversight of the research process with
an eye on maintaining the protection, safety and welfare
of the research subject volunteer. Beecher Article
In 1966, Dr. Henry K. Beecher was an anesthesiologist
who wrote an article in the NEJM describing 22
examples of unethical research conducted and published
by "reputable" researchers of the time. He wrote,
"medicine is sound, and most progress is soundly
attained," however, if unethical research is not
prohibited it will "do great harm to medicine." At that
time it was assumed that the only unethical research was
that which went on in the Nazis' prison camps. Tea Room Study
In the 1960s, there was a study on the homosexual
practices in public restrooms, then, to contact the men
at a later time to conduct further investigation on
their behavior. The researcher went undercover and
gained the confidence of the gay men. He identified 100
active participants by tracing their car license
numbers. A year after he completed the initial study, he
distributed a "social health survey" throughout the
communities where he knew the participants lived. The
ethical problems were: use of a vulnerable population,
reinforced the image that social scientists use
deception casually in research, and lack of proper
informed consent. Humphreys,
Laud. Tearoom Trade: Impersonal Sex in Public Places.
Walter de Gruyter, Inc, February 1975. The Belmont Report Released in 1979
by the National Commission for the Protection of Human
Subjects of Biomedical and Behavior Research, it
provided more strenuous protection to human research
subject volunteers. It was entitled
Ethical Principles and Guidelines for Research
Involving Human Subjects.
It was preceded by the
National Research Act that legislated
formation of IRBs in reaction to the
Tuskegee Syphilis Study conducted by the United
States Public Health Service back in 1932 involving poor
blacks in rural Alabama who were enrolled in an
observational study of the natural history of untreated
syphilis. The men were recruited without informed
consent and, in fact, were misinformed that some of the
procedures in the interests of research (spinal taps
were explained as back shots) were actually "special"
free treatments. By 1936 it had already become apparent
that many more infected men than controls had developed
complications. In the 1940s penicillin was determined to
be efficacious for syphilis. This study ended in 1972
when a reporter exposed the horrors of untreated
tertiary lues. President Clinton issued a formal apology
a few years ago to the families of the over 400 black
men with syphilis and the 200 men without syphilis who
served as health controls who were victims of the
prolonged and knowing violations of the rights of a
vulnerable group of research participants. The
Belmont Report pointed out the differences between
"practicing medicine on patients" and "performing
medical research on human research subject volunteers."
It cautioned researchers to think about what hat they
were wearing at any particular time. It identified three
basic principles to guide researchers to provide safer
medical research:
Respect for persons
Beneficence
Justice
Respect for persons is the principle
involving recognition of the personal dignity and
autonomy of individuals and the need for special
protection to be afforded to those with diminished
autonomy. That is, the person has to understand what
they're getting into. Autonomy is protected by the
consent process. Each prospective subject must be given
ample time and information to decide whether to
participate or not in a research study. There is need
not only for initial consent, but also for an ongoing
and continual informed consent process as the study
progresses.
Obtain Informed Consent
Respect the privacy of research subjects
Does the consent process and protocol maximize
autonomy?
Additional protections put in place to
safeguard vulnerable populations
The study needs to maximally protect subject
privacy
Need to adequately inform subjects of
potential risks
Beneficence or the lack of malficence has to
do with not doing harm and maximizing benefits.
Explaining the risks, benefits and alternative treatment
options available. This principle is the basis for the
risk/benefit ratio assessment in which principal
investigators, sponsors, CROs, IRBs and Independent
Ethics Committees (IEC) and institutions all seek to
ensure that any risks are minimized, and not taken
unless there is likely to be a benefit to the individual
research subject volunteer.
Use the best possible research design to
maximize benefits and minimize harms
Make sure the researchers are able to perform
the procedures and handle the risks
Research without a favorable risk/benefit
analysis may not be conducted
Looking to see if adequate research designs
can be improved further
Identifying and minimizing risks
Identifying and maximizing benefits
Justice has to do with how researchers
distribute the burdens of research and who actually
receives the benefits. For example, do you include only
poor people in a study that would only have benefit to
rich people? Therefore, the principle of distributive
justice requires that both the burdens and the benefits
of research be distributed equitably. Subject selection
should be based on those who stand to bear the risks
should also be the ones who will benefit from the
research.
Select subjects equitable: recruitment targets
the population that will benefit from the research
Avoid exploitation of a vulnerable population
or a population of convenience
Does the recruitment unfairly target a
population?
Are the inclusion/exclusion criteria fair?
Autonomy/respect to decide whether to
participate or withdraw from a study
The Code
of Federal Regulations
In 1980, the Food and Drug Administration established
regulations on the protection of human subjects. These
can be found in the Code of Federal Regulations (CFR),
Title 21, Part 50, commonly abbreviated as 21CFR50.
Institutional review board information can be found at
21CFR56.
CIOMS Guidelines
In 1982, the Council for the International Organization
of Medical Sciences (CIOMS) published the International
Ethics Guidelines for Biomedical Research Involving
Human Subjects. These are designed to guide researchers
from the more technologically advanced countries when
conducting research in developing countries. It allows
for cultural differences in ethical standards. Office of Research
Integrity
In March 1989, the Public Health Service (PHS) created
the Office of Scientific Integrity (OSI) and the Office
of Scientific Integrity Review (OSIR). These offices
were to deal with scientific misconduct from the funding
agencies. In May 1992, OSI and OSIR were consolidated
into the Office of Research Integrity (ORI). The Common Rule
The Common Rule was enacted in 1991. It is the Federal
Policy for the Protection of Human Subjects. It covers
research supported by the Departments of Agriculture,
Energy, Commerce, HUD, Justice, Defense, Education,
Veterans Affairs, Transportation, and HHS as well as
NSF, NASA, EPA, AID, Social Security Adminstration, CIA,
and the Consumer Product Safety Commission. The
provisions are identical to the DHHS Regulations
(45CFR46, Subpart A). Death of a Normal Volunteer
On March 31, 1996, a 19-year-old female Asian-American
student at the University of Rochester responded to an
advertisement for study patients to undergo bronchoscopy
for the harvest of alveolar macrophages. The patient
died of an overdose of lidocaine. The protocol didn't
limit the dose. The pulmonologist didn't record the
amount of lidocaine administered.
Food and Drug Administration Modernization Act of 1997 Further
improved regulation of drugs to ensure their purity,
safety and efficacy. Death on Gene Therapy Trial
In the fall of 1999, 18-year-old Jesse Gelsinger died
as a result of his participation in a gene therapy
trial. Jesse had a rare metabolic disorder, ornithine
transcarbamylase deficiency syndrome (OTC), which was
being controlled with diet and medication. Researchers
were testing an innovative technique using adenovirus
gene therapy. Shortly after treatment Jesse experienced
multiple organ failure and subsequently died. This case
catapulted research with human subjects into the
national media. Serious concerns related to conflict of
interest, data safety monitoring, and informed consent
have made the Gelsinger case the most contemporary
illustration of continued doubts about the ethical
integrity of research with human subjects. This case has
instigated deliberations on all these controversial
topics at the national level. The outcome of such
discussions have yet to be determined. Veterans
Administration
In April 1999, all research projects at the Veterans
Administration West Los Angeles Medical Center were shut
down after many allegations of medical research
performed on patients who did not consent. An
investigation showed that not only was research being
done on patients without who had not given informed
consent, but also that research was being done on
patients who had expressly refused consent. Duke University Medical Center
On May 12, 1999, the federal government ordered
Duke Clinical Research
Institute to stop its research due to problems with
its IRB. The order was issued by the US Department of
Health and Human Services'
Office for
Protection from Research Risks (OPRR). The Office of
Human Research Protections
The Office of Human Research Protections (OHRP) was
established in 2000 with the US Department of Health and
Human Services to increase the focus on protecting human
research participants. Death of a Healthy Research Subject Volunteer
Ellen Roche was a 24-year-old healthy research
volunteer enrolled in an
experimental drug study at
Johns Hopkins Medical Center who died on June 2,
2001, following her participation in an asthma research
study where she inhaled hexamethonium.
The New York Times
reported she died because of failure of scientists and
administrators to recognize that the experiment was
unsafe. All research there was halted until the
following actions were taken to strengthen research
oversight:
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"A foolish faith in authority is the worst enemy of truth."
-- Albert Einstein, letter to a friend, 1901
"I know of no safe depository of the ultimate powers of the society but the people themselves, and if we think them not enlightened enough to exercise control with a wholesome discretion, the remedy is not to take it from them, but to inform their discretion by education."
-- Thomas Jefferson, letter to William C. Jarvis, September 28, 1820
"What's the point of vaccination if it doesn't protect you from the unvaccinated?"
-- Sandy Gottstein
"Who gets to decide what the greater good is and how many will be sacrificed to it?"
