Human Subjects Research Training: "Protecting Human Subjects" - Module 1

Uploaded by HRSAtube on 08.03.2012

(female announcer)This is part of a series of videotapes
intended to help health professionals understand their responsibilities
for protecting human subjects in biomedical and behavioral research.
One program discusses the criteria used by IRBs
for reviewing research. Another shows how to apply the basic ethical
principles which underlie the involvement of human subjects.
The series begins with this program, which looks at the historical backdrop of
concern for human subject protection.
It then follows the evolution of these concerns toward present-day practices.
(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, 5:18. signed by the subject as well as the researcher.
(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 a 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. 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"--
The court, in condemning these doctors, accepted and codified ethical standards
that the defendants had grossly violated. These standards came to be known’s 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 constraint he 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.
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." 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 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.
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 expressedin the story of Abraham.
In the experiment, the subject was told to givewhat appeared
to the subject to be an electrical shockto 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.
It is potentially harmful to a subject to commitin 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 usedto stimulate these actions.
The subject realizes he would have hurt the victim
if the current were on. Much valuable criticism of research practices
has come from withinthe research community. In 1966, Dr. Henry K. Beecher,
a Harvard Medical School teacherand respected researcher,
raised ethical questions in an article in The New EnglandJournal 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:
Pappworth, in England, has collected, he says, more than 500 papers based uponunethical experimentation.
It is evident from such observations that unethical or questionably ethical procedures
are not uncommon. All so-called codes are basedon the bland
assumption"-- In the same year, the work begunby 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-- To assure an independent determination
of the protection of the rights and welfare of the individual or individuals involved.
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 understandthat 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.
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 benefitswhile 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.
If they decide they do not want to participate, is there any coercion?
If that's an issue, then it's--the whole study'san issue, because--
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 researchon 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.