[Male Narrator] In 1926, Paul de Kruif published Microbe Hunters, a popular history of biomedicine.
In it, he portrayed researchers such as Louis Pasteur and Walter Reed as independent visionaries
struggling alone to understand and conquer disease.
We start our examination of concern for protecting human research subjects by recalling de Kruif's
popular book, because it represents a transition.
The great researchers of the past worked alone and took sole responsibility for their experiments
with humans.
But the entire scale of research was expanding.
By the second half of the 20th century, science had provided numerous new techniques in the
diagnosis, prevention, and cure of disease.
Public appeal and support encouraged even more research.
The number of experiments, and thus the number of human subjects, dramatically increased,
and scientists were in the forefront of those reminding us of our responsibility to research
subjects.
Researchers were increasingly concerned that the growing numbers of subjects receive adequate
protection from risk.
Given the increasing complexity and scale of scientific research, some began to wonder
if possible negative effects from the research might go undetected.
In many instances, independent committees of researchers were formed to review proposed
research from an ethical perspective.
Increasingly, government, scientists, and the public agreed on the need for strengthening
protection of research subjects.
Today we recognize that human subject protection is the shared responsibility of many: clinical
investigators, institutions, government officials, and the Institutional Review Boards, or IRBs.
The IRB is a committee of scientists and nonscientists at the local level that reviews research protocols
and consent forms to ensure that the rights and welfare of research subjects are protected.
To understand the multifaceted roles involved in assuring these protections, one must look
at the recent history of medical and behavioral research.
Part of that history are the key events that resulted in the protective mechanisms we have
today.
There was no clear first step in this evolution of concern for the rights of research subjects.
Antecedents appear during the 20th century and before.
This consent form from the year 1900, though, serves as a point of departure.
The form was used for the yellow fever experiments that made Walter Reed famous.
It was provided in both Spanish and English, signed by the subjects well as the researcher.
[Man] “…Understand…that he endangers his life to a certain extent but it being
entirely impossible for him to avoid the infection during his stay in this island he prefers
to take the chance to contracting it intentionally…”
[Narrator] The form was evidence that Reed believed sound ethical practices go hand in
hand with research involving human subjects.
Ethical concern has deep roots, back to the do-no-harm principle attributed to Hippocrates.
Protecting research subjects has been long-standing basic tenet of experimental medicine.
But medical research is characteristically frustrated by blind leads, ambiguous results,
and negated hypotheses.
Yet there is pressure to continue medical progress, and occasionally, investigators
have been inadequately sensitive to the need to protect the interests of those who are
actually at risk, the research subjects.
As we follow the evolving concern for research subjects, we will encounter some occasions
when subjects were not adequately protected.
Such examples of research constitute a tiny minority of experimental work, but they did
stimulate researchers and the public to improve systems for protecting research subjects.
In December 1946, 23 medical professionals from Nazi Germany went on trial in Nuremberg.
They are important because their actions precipitated the first modern effort to formulate an international
code of ethics protecting human research subjects.
[Man] “The victims of these crimes are numbered in the hundreds of thousands.
A handful, only, are still alive.
A few of the survivors will appear in this courtroom, but most of these miserable victims
were slaughtered outright or died in the course of the tortures to which they were subjected."
[Narrator] The offenses ranged from subjecting prisoners to extremes of altitude and cold
to using them as human typhus and malaria cultures for testing vaccines.
[Man] "It is our deep obligation to all the peoples of the world to show why and how these
things could happen.
It is incumbent upon us to set forth with conspicuous clarity"—
[Narrator] The court, in condemning these doctors, accepted and codified ethical standards
that the defendants had grossly violated.
These standards came to be known as the Nuremberg Code, the first internationally recognized
code of medical research ethics.
The code sought not merely to prevent experimental abominations in the future but to increase
the protection of the rights and welfare of human subjects everywhere by clarifying the
standards of integrity that constrain the pursuit of knowledge.
The code was a guide, not a law.
The first of its ten principles stresses the necessity for voluntary informed consent from
research subjects.
It defines the meaning of informed consent and places the responsibility for obtaining
adequate informed consent on the researcher.
Other points include: experiments should not be random or unnecessary, experiments with
humans should be preceded by experiments on animals and surveys of the natural history
of the disease, unnecessary physical and mental suffering should be prevented, experiments
should be conducted by scientifically qualified professionals, subjects should be permitted
to withdraw at any time, and investigators should be prepared to stop an experiment at
any time if the subject is endangered.
The Nuremberg Code enumerated the fundamental principles that ought to guide research involving
human subjects, but it was not the last word.
Although the role of informed consent seemed clear enough in biomedical experiments, this
was not always the case for other research involving human subjects.
In the early 1950s, the Wichita, Kansas, Bar Association became concerned about articles
in a nationally syndicated column suggesting trickery when lawyers argue before juries.
The Wichita lawyers wanted reliable information on how juries deliberate and reach decisions.
At the same time, the University of Chicago received a Ford Foundation grant to study
a variety of legal issues, including jury behavior.
In 1953, with the cooperation of the U.S. 10th Circuit Court of Appeals, and approval
of lawyers on both sides, University of Chicago researchers recorded six jury deliberations
without the knowledge of the jurors.
The transcripts were carefully guarded, and names in the cases were changed to protect
the identity of all involved.
In 1955, Senator James O. Eastland, brought this matter before the Senate Internal Security
Subcommittee.
How could researchers justify recording jurors without first obtaining their permission?
Behavioral scientists at the University of Chicago defended the study by explaining that
prior knowledge of the recording by the jurors would alter their behavior.
Others agreed with The Washington Post.
[Woman] "A jury imperatively needs to carry on its deliberations in private.
When it retires to consider the evidence, its members must be free from any outside
pressure or fear of reprisal."
[Narrator] After weighing the arguments, Congress enacted legislation prohibiting the recording
of juries in federal courts.
Behavioral researchers were required to respect the fundamental rights of the public in their
research.
At about the same time the juries were being taped in Wichita, the National Institutes
of Health was opening a new clinical research center in Bethesda, Maryland.
Rules of the new research hospital required a panel of qualified scientists to review
the protocol for any research involving healthy volunteer subjects.
Other institutions also were beginning to form committees to review research.
These were often informal groups convened by the scientists themselves to discuss ethical
aspects of research.
These boards were to some degree an innovation.
They were not the Institutional Review Boards of today.
They did not, for example, include members from the community, but they were a step toward
the IRB.
In the early 1960s, a new drug, thalidomide, was introduced for experimental use in the
United States.
It had been prescribed extensively in Germany and England.
The 1938 Food, Drug, and Cosmetic Act allowed pharmaceutical companies to distribute new
drugs for testing without FDA review.
In the thalidomide case, it is estimated that more than 1,000 doctors in the U.S. administered
the drug.
Many of these doctors did not tell their patients the drug was experimental.
When it was discovered that thalidomide taken by pregnant women could produce tragic deformities
in the fetus, there was a wave of public reaction, and the use of the drug was stopped.
The Kefauver-Harris hearings resulted in the 1962 amendments to the Food, Drug, and Cosmetic
Act, which included requirements that investigators must inform potential subjects of the experimental
status of the drug and obtain consent.
In requiring consent, Congress allowed the physician to decide whether or not obtaining
consent was in the best interest of the subject.
The new amendments and the resulting regulations were a major step in the developing concept
of informed consent by subjects.
The protection described in the Nuremberg Code was evolving and becoming mandated through
congressional legislation and government regulation.
In 1963, another landmark incident furthered the evolution of concern for research subjects.
A group of well-respected physicians from the Sloan-Kettering Institute approached the
medical director of the Jewish Chronic Disease Hospital in Brooklyn seeking help with a study
of the immune system in cancer patients.
The research protocol required injecting live cancer cells under the skin of feeble and
seriously ill patients.
The injections were given.
Apparently, the patients were told their resistance was being tested.
They were not told the injections contained live cancer cells.
The story would have remained untold had a non-physician on the hospital board not inquired
about the propriety of injecting patients with cancer cells and had he not taken the
hospital administration to court to obtain access to the patients’ medical records.
Once the lawsuit drew public attention, the research was severely criticized because of
its failure to respect the research subjects.
Had the physicians betrayed their patients' trusts?
Were not the doctors facing conflict between their obligations to their patients and their
desire to obtain research results?
The civil rights movement and the social climate at that time encouraged an increased concern
for all human rights.
Whether the subjects were elderly people, poor people, children in institutions, or
prisoners, researchers could expect criticism if the individuals' rights were not respected.
During the late '50s and '60s, Dr. James Shannon, director of the NIH, conceived a study to
determine how to protect research subjects adequately.
In 1964, he appointed a committee to review the study and design mechanisms to ensure
that subjects would be systematically and uniformly protected in all biomedical and
behavioral research funded by the Public Health Service.
About the same time, with the public recalling American prisoners of war being brainwashed
during the Korean War, debate over the safety of psychological research intensified when
Yale University investigators published a paper entitled “Conditions of Obedience
and Disobedience to Authority.”
[Man] “The situation in which one agent commands another to hurt a third turns up
time and again as a significant theme in human relations.
It is powerfully expressed in the story of Abraham –“
[Narrator] In the experiment, the subject was told to give what appeared to the subject
to be an electrical shock to another person for the stated purpose of studying the effects
of punishment on learning.
This allowed the investigator to observe the subject's willingness to carry out orders
even if they resulted in pain or harm to others.
No electrical shocks were actually administered.
Afterwards, the principal investigator carefully explained the real purpose of the events to
the subject.
The study caused a furor.
In The American Psychologist, Dr. Diana Baumrind, a behavioral scientist, spoke for many.
[Woman] "It is potentially harmful to a subject to commit in the course of an experiment acts
which he himself considers unworthy, particularly when he has been entrapped.
The subject’s personal responsibility for his actions is not erased because the experimenter
reveals to him the means which he used to stimulate these actions.
The subject realizes he would have hurt the victim if the current were on."
[Narrator] Much valuable criticism of research practices has come from within the research
community.
In 1966, Dr. Henry K. Beecher, a Harvard Medical School teacher and respected researcher, raised
ethical questions in an article in The New England Journal of Medicine.
From published research papers, he cited serious ethical problems in the protection of human
subjects in numerous cases.
In some of them, the controls were denied treatment.
In others, risky surgical procedures were attempted.
Dr. Beecher concluded:
[Man] "Pappworth, in England, has collected, he says, more than 500 papers based upon unethical
experimentation.
It is evident from such observations that unethical or questionably ethical procedures
are not uncommon.
All so-called codes are based on the bland assumption –“
[Narrator] In the same year, the work begun by Dr. James Shannon found fruition in a policy
statement by the surgeon general of the United States that all research funded by the Public
Health Service undergo prior review by an investigator’s institutional associates.
[Man] "To assure an independent determination of the protection of the rights and welfare
of the individual or individuals involved."
[Narrator] In 1972, public attention again focused on research subjects.
The Public Health Service study on the effects of untreated syphilis, conducted in Alabama,
received extensive media coverage.
The study, widely but misleadingly called the Tuskegee study, started in 1932 as an
offshoot of an experimental program in which nearly 300 black men with syphilis were followed
to determine the natural course of the disease.
The men did not understand that they had syphilis or that they were participants in a research
study.
They were not offered treatment even after penicillin became available.
Although the experiment was originally intended to last only a few months, it was continued
for 40 years.
The study was the most visible of several projects discussed by the Senate Health Subcommittee.
Senator Edward Kennedy and others heard testimony from the scientific community as well as from
research subjects.
They testified that human subjects needed additional protections.
As a result of the hearings, Congress passed the National Research Act of 1974.
One of the requirements was the establishment of Institutional Review Boards to review all
HEW-funded human research.
Another result was the establishment of the National Commission for the Protection of
Human Subjects of Biomedical and Behavioral Research.
The National Commission was a diverse group representing both science and society.
Its detailed reports explored ethical considerations in human experimentation and were widely viewed
by the media and public as authoritative.
In 1978, it issued what has become known as The Belmont Report, which summarizes the basic
ethical principles which underlie research.
It discusses those principles: respect for persons, maximizing possible benefits while
minimizing possible harms, and justice in sharing the risks of research among those
who will benefit from it.
It discusses the application of these principles to informed consent, assessment of risks and
benefits, and selection of subjects.
[Man #1] If they decide they do not want to participate, is there any coercion?
[Man #2] If that's an issue, then it's--the whole study's an issue, because—
[Narrator] Despite the establishment of IRBs and the heightened awareness of researchers,
the concern for protecting research subjects continues to prompt study and debate.
There continues to be uncertainty about the limits of research on special populations
such as prisoners, infants, or the mentally incapacitated.
There is dispute about the legitimacy of various kinds of behavioral research, and there is
ongoing consideration of the need for additional regulations and of the way IRBs function.
The refinement of our methods of protecting human subjects thus continues, as it must.
Ultimately, it is the conscientiousness of the IRB and the researcher that will protect
all of us: the research institution, the research subject, and a society that benefits from
research.