Human Subjects Research Training: “Protecting Human Subjects” – Module 2
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Human Subjects Research Training: “Protecting Human Subjects” – Module 2


This country has always been considered a
melting pot. People from many nations and ethnic traditions
have come here. They brought with them varied religions,
philosophies, and concepts of right and wrong. Our nation reflects
this diversity of peoples and principles. We’ve created a government of consensus
in part to accommodate the diversity of ideas thrust into our melting pot.
Some issues are resolved more easily than others.
Our history is replete with clashing values. For resolution, we turn to a variety of institutions:
government, the courts, the press, academia. Ideas have become institutions too:
our Constitution and Bill of Rights, a body of law
and the various Western ethical and philosophical traditions.
These provide the principles, the ground rules through which our problem-solving
institutions can all agree to work.
Research, too, is an institution. The principles which guide it, however,
have never been as well-defined as the bill of rights.
In the early days, research relied mainly on the integrity of the professional.
Researchers invoked the benefit to society and the need for progress
to justify asking volunteers to bear research risks for all.
By the early 1970s, various congressional bodies
had heard complaints. basic protections weren’t being given
to people participating in research. A frustrating paradox emerged.
Researchers were making great progress in relieving pain and suffering.
Yet human research subjects in a few well-publicized experiments
clearly lacked protection. Everyone–Congress, researchers, and the public–
needed reassurance that abuses would be prevented. How would we deal with potential threats
to human values in new realms of investigation? Genetic research,
behavior-modification techniques and drugs, mood-altering drugs,
and interventions such as organ transplants and artificial hearts?
America was on the threshold of a biological revolution.
It had the potential to be as socially disruptive as those sparked by Copernicus, Darwin, Freud,
or the splitting of the atom. How would we protect
certain groups of research subjects that previously lacked adequate protect?
The poor, disadvantaged, ethnic minorities, prisoners, children, the mentally disabled,
and the unborn? Congress was being called upon to draft new
legislation to cover problems which might arise
at the frontiers of research. It responded by creating a national commission,
a forum which would come to grips with both the specific problems faced by researchers
and the need for a basic statement of ethical principles to guide new biomedical
exploration. No matter what new directions
science and technology might take in the future, Congress wanted flexible review criteria established
that would protect human research subjects. They wanted to do for research
what the Bill of Rights was doing for so many other areas of human endeavor.
The Commission began by studying populations requiring special protection.
Then it moved onto the broader congressional mandate:
Identify fundamental ethical principles which guide research.
To do so, the commission paused for reflection at a conference center outside Baltimore,
the Belmont Center. The report that emerged in 1978,
following additional monthly deliberations, was known as The Belmont Report.
It articulated three basic ethical principles underlying all research involving human subjects.
Actually, these principles have been part of philosophical discourse
and our Western heritage since the Greeks, but uniquely, The Belmont Report tied each
principle to concrete research applications.
Today, a decade later, these eight pages continue to be a standard reference
for investigators and Institutional Review Boards.
Of many possible principles, The Belmont Report singled out
respect for persons, beneficence, and justice. These three are comprehensive enough
to capture the ethical values inherent in good research.
Respect for persons incorporates at least two ethical convictions
from our democratic heritage. Individuals should be treated as autonomous
agents. Autonomy means a person can think clearly
about personal goals. He or she is capable of making choices
after careful consideration of all information. So the medicine is a medicine
that actually would slow down the hormones of puberty
while you’re still growing taller, and the process of puberty would actually
stop for a while while you’re taking the medicine.
Subjects would be dealt with fairly and openly. To deny someone autonomy
is to deny them respect as an individual. But some people do not have the capability
of self-determination, of autonomy because of illness, mental disability,
age, or immaturity. They require special protection,
because they may not be able to choose for themselves.
But The Belmont Report does not stop with this abstract principle.
It explains a way to implement respect for persons:
informed consent. It then goes on to suggest
several minimum components of informed consent, such as information, comprehension,
and voluntariness. Okay, but usually we have–
when we decide to have a young person go on a study,
we have them actually sign the papers that I sent you.
Do you feel like you’d like to sign it now, or would you rather wait till tomorrow
when we go over it and see what other questions there are?
Well, I could sign it now. Well, we’ll wait.
Okay, we’re gonna be back tomorrow anyway. So we’ll talk–
The Belmont Report lists detailed consent criteria
stating facts isn’t enough. Is the information offered in the consent
process sufficient for people to decide
whether they want to participate? Subjects must understand
the extent of the risk they are taking. They must know that participation is voluntary,
that they can withdraw from the research at any point if they choose.
Maria, we have three problems in your brain. [woman speaking Spanish]
But information, even complete information, without comprehension is insufficient.
Does the subject understand adequately? There are often cultural, language,
and educational factors that interfere with communication
and the ability of the research subject to understand.
[woman speaking Spanish] [Maria speaking Spanish]
[woman speaking Spanish] (man) What is she asking?
(woman) She’s asking– she doesn’t understand why it’s happening,
this. Respecting the person
means respecting and dealing with the individual’s ability to understand.
An investigator must meet and deal with subjects on their own terms.
Consent must be free of coercion or undue pressure.
Belmont asks where does justifiable persuasion end
and undue pressure begin? The brain makes several substances
we call neurotransmitters. These are the chemicals that the brain cells
produce to use to communicate with one another.
(man #2) Mm-hmm. (man #1) We know that in Alzheimer’s Disease,
some of these neurotransmitters are deficient, and what we’d simply like to do is to put
some of them back and see if it improves the person’s condition.
When understanding is inherently impaired, as with the mentally impaired,
or not yet developed, respect requires giving them the opportunity
to the extent that they are able to choose whether or not to participate.
The second principle is beneficence. Subjects place great trust in investigators.
Following the principle of beneficence helps validate that trust.
The major hazard is that your thyroid gland will take up large amounts
of the injected radioactive iodine. This is prevented by the daily administration
of iodine-containing solution before and during the study.
Okay, any questions at this point? About what is the half-life of the radioactive
tracer? The Hippocratic maxim Do no harm has long
been a fundamental principle of medical ethics.
However, avoiding harm requires learning what is harmful.
The process of obtaining this information may expose people to risk.
The Hippocratic oath also requires physicians to help or benefit their patients
according to their best judgment. This is what Belmont calls beneficence.
The problem posed by these imperatives is to decide when it is justifiable
to seek certain benefits despite the risks involved
or when the benefits should be foregone because of the risks.
This principle has a parallel application: assessment of risks and benefits.
There are two steps in the assessment. Investigators and Institutional Review Boards
should first define the nature and scope of risks and benefits
and then systematically assess them, weighing risk against benefit.
Ordinarily, quantitative techniques will not be available to measure risks
entailed by research procedures. However, as far as possible,
there should be systematic nonarbitrary analysis of the risks and benefits.
Finally, The Belmont Report looks at justice. Who should receive the benefits of research?
Who should bear its burdens? And for any research, how can we be sure
the risks are distributed equitably? During the 19th and early 20th centuries,
the burdens of serving as research subjects fell largely on poor ward patients.
They often received good care, but private patients were less frequently
called upon. The burden was unequal.
Today our sense of justice makes us scrutinize the selection
of research subjects more carefully. Are some classes of patients–
welfare recipients, minorities, or inmates of institutions–
being selected simply for easy availability and manipulation
rather than for reasons related to the research? The Belmont Report has been and continues
to be widely read. Researchers and members of Institutional Review
Boards should consider it a required reference work.
How are the Belmont principles applied? How are they inherent in good research?
For an answer, we go back to the early 1970s. Researchers were keenly aware of the need
to prove the efficacy of new drugs or procedures. Social responsibility demanded it.
Randomized clinical trials were the method of proof.
At NIH, Dr. Carl Kupfer was preparing to test a widely used but unproven eye treatment.
(Kupfer) Only by doing a randomized-control clinical trial can we determine
in a very scientifically valid way and without any equivocation,
whether a particular treatment modality whether it’s a new drug or a new surgical
intervention is a benefit to the patient.
Diabetics frequently experience small hemorrhages in the retinas of both eyes
as a consequence of diabetic retinopathy. With the availability xenon arc and argon
laser energy sources, ophthalmologists had experimentally burned
away this damaged tissue.
The procedure was call photocoagulation and was believed to slow or stop the progress
toward blindness. But the efficacy of the treatment
had never been shown. In fact, photocoagulation
conceivably could damage the eye. In a randomized clinical trial,
researchers set out to validate the procedure. Dr. Frederick Ferris was one of the investigators.
(Ferris) And it occurred to us that perhaps you could
have your cake and eat it too, in a sense, particularly from the patient’s point of view,
because we weren’t sure whether the new treatment was better than no treatment at all,
we weren’t sure what all the risks of treatment were,
and we weren’t sure what all the benefits of treatment were.
With this kind of design, where we could do one treatment in one eye
and the other treatment in the other eye, I think we were aware that we really could
provide for the patient some of both,
a little bit of having your cake and eating it too,
because if it was true that the new treatment was harmful,
well, we wouldn’t harm both eyes. If it was true that it was beneficial,
at least one eye would have received the benefit of photocoagulation.
And therefore, whichever turned out to be better,
the patient would have received the better treatment.
Society has the right to require that a particular procedure
be shown to do good– beneficence, in the language of Belmont.
Dr. Kupfer and his fellow researchers sought to demonstrate whether or not
photocoagulation is beneficial. Beneficence also requires that research subjects
be unharmed by their participation. Do no harm.
These two moral imperatives are not opposites or mutually exclusive.
They’re simply parallel issues, both of which must be addressed.
The team also was concerned with the respect for persons
through the process of informed consent. (Kupfer) Because in a sense, the informed
consent is inextricably bound up with the ethical
question. If a physician can honestly sit down with
the patient and explain the informed consent
and all the potential benefits and all the potential adverse effects of the
treatment and be convincing to the patient,
that means, first of all, the physician believes this,
and secondly, only if it is truly ethical and the physician feels that in his own heart
can he convince the patient to go ahead and enroll in such a study.
That could be of a serious nature. What happens in diabetic patients
is that the tiny little capillaries, the little blood vessels that nourish the
retina get narrowed down.
The study was designed to follow patients for up to five years.
They returned for examination every few months. Consent needed to be an ongoing process.
You’ve had a small hemorrhage in your untreated right eye.
It’s relatively small. I can’t tell for sure where it’s coming from,
but I suspect it may be from the new blood vessels
on the nerve of vision. I think it will probably clear in a couple
of months, but the long-range outlook
will depend upon how many more hemorrhages you have.
Would you treat my right eye now or sometime later?
Well, the doctors that are monitoring the results of this study
tell us that, to date, there’s no clear evidence that treatment is either beneficial or harmful.
So I think we should stick to our original decision
to just treat your left eye and not do any treatment to your right eye.
(Ferris) We told them that as data accumulated in the trial,
it may become evident that one treatment was better than the other,
or treatment was better than no treatment. And we told them that
as soon as that information became available and it was clear-cut that one was better than
the other, we would inform them
and we would do whatever was appropriate with the other eye.
If it had turned out that treatment was dangerous, of course, we wouldn’t have done anything
to the other eye. As it turned out, about a little over two
years into this study,
it became clear that treatment was better than no treatment.
Of course, central to the study’s capacity to keep
the research subject informed was an ongoing data-monitoring program.
(Kupfer) Another aspect of ethics which I think is terribly important
and is built into every clinical trial is the use of a data and safety monitoring
committee. This is a group of individuals who are knowledgeable
but outside the study who look at the data every four months,
six months, eight months, depending on how that data is coming in
and decides when that clinical trial should be stopped
either because there’s a clear benefit from the intervention
or because there may some very serious adverse effects
or when the protocol might be changed to accommodate some new development.
Watch the red light, Jen. Seeing the Belmont principles as a legalistic
test for compliances or noncompliance is to misdirect
them. Rather, they are intellectual tools
the IRB can use to articulate issues and then adjust the protocol
for the greatest possible protection of the research subject.
Now, it’s important that we understand some of the things that happened that evening.
And what I want to ask you is– Social problems also are a fertile area for
research. Our next case study looks
at how the Belmont principles can be applied to a one-year longitudinal study
of anxiety reactions to sexual assault. Victims of social violence
are the source of much valuable information, but researchers must take great care
to minimize the additional stress caused by research questions.
So they’ve got intervene in the first two– These two IRB members have been invited
to review a proposal for the study conducted by a university psychology department.
Two groups will be interviewed: women selected through a hospital emergency
room sexual assault center
and a comparison group using the emergency room
for primary medical care. Even at this screening stage,
care must be taken to respect the potential research subject.
The women from the assault center will know why they are being asked personal
questions, but what about the women
being recruited for the comparison group? They, too, are being asked very personal questions
to screen out those who’ve experienced social violence.
How are they protected? There’s some pretty explicit questions in
there, and if the researcher doesn’t know,
that’s asking questions and doesn’t know that a person is a rape victim,
all of a sudden, the person may begin reacting to some of the questions and getting upset
by them. Well, they’re going to have to build in some
procedures for stopping the interview,
for handling any kind of discomfort that comes up during the interview,
but they’re also going to have to provide some follow-up care, not treatment,
but some kind of follow-up procedures for these people who might get upset
by discussing things that happened in the past.
A person’s response to probing questions can’t always be predicted.
The researcher’s questions may trigger emotional stress in the individual.
Not only must interviewers be trained to be sensitive
to the feelings and circumstances of both victims and the comparison group;
they also must know how to safeguard confidentiality. That anything said to the researcher
will not in fact go back to either the rape crisis center
or to the hospital. The best way for this person to accomplish
that would probably be to actually be doing the
interview somewhere other than hospital property
that would reemphasize to the patients or to the clients
that their records are separate. So at this point, he’s proposing to sit–
she’s proposing to sit in a room in the hospital, and I think that we should recommend
that the research interviews be done somewhere else.
(woman #2) You know, the other thing I noticed that really concerned me a lot is that the
consent form is filled with, like, promissory notes.
We guarantee full confidentiality, and the like, but they don’t really outline
what the protections are. It’s simply a take it on faith,
and I think the researcher needs to think through
more than just good intent the actual procedures. Now, that would be one example:
where it would– where the interviews would be held
and who would have access to the information. Many questions need to be asked
about the entire consent process. There are several steps involved.
This study lasts a year. Each visit by the subject requires consent.
You know, something else I thought about when you mentioned a person being able to–
and to be told ahead of time that they can withdraw
or not answer any questions, you should probably also–
which they don’t have in their protocol– have a multistage consent.
Even though–each time that you don’t assume that the first time that the person gives
consent, until they actually know what the questions
are, it’s very difficult to know
exactly what you’re giving consent to, and it would be good to make sure that, each
time, you reexplain what it is you’re doing,
and explain each time, because they’re going to forget
over a period of three months since the last time
that they can withdraw or can refuse to answer questions.
The principles stated in The Belmont Report apply to behavioral and social science research.
They are a tool rather than absolutes. This program began with the idea
that research is taking its place as an institution in our society.
It joins government, the family, academia, and free speech
as institutions that protect our values in the face of change.
We made an analogy between ethical principles and the Bill of Rights.
Both are statements of principle which help guide their respective institutions.
The Belmont Report is one resource among many. It is applied to research issues
along with a host of other professional codes, statements of principle, and regulations.
The Belmont principles stand apart, however, because they have a flexibility that codes
do not. Rather than setting forth rigid prohibitions,
the report encourages debate and careful consideration. IRB members and investigators
are committed to the rights of individuals, but determinations made by IRBs and investigators
would be limited if they relied only on their personal resources.
The Belmont principles enlarge the debate. They encourage breadth and depth.
The principles represent a consensus going back to the Greeks.
(Sabin) A scientist doing research in order to solve problems of importance to
human beings and the resolution of the unknown of human
disease has very high principles to begin with.
And I’ve had to use human subjects during the course of my career
for getting many other kinds of answers, but there were two basic principles.
In the first place, can the answer be gotten in any other way?
And if the answer is no, then you must approach
the use of human subjects, volunteers. And the second question was, is it necessary?
Is it important enough? Because if it is not important enough,
I felt, personally, there was never any justification
to use volunteers. The
concept of human dignity is what inspires
research. Disease of any sort is an offense against
dignity. Scientific advances, then, must be made with
no compromise to the dignity of research subjects.
Good science and good ethics go hand in hand.

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