[Woman 1] These protocols, you know these new investigators, especially these multiple-center
protocols, are really getting to be a problem.
I don’t know if we should try and develop some sort of checklist or something like that,
but you know, the third time in it seems like, you know, we would not have to go through
so much.
Let’s just take a look at this one one more time, and see, can we get it straightened
out.
[Woman 2] Sure, it’s a multi-center protocol, you’ve seen it before.
We didn’t get enough information human subjects part of the protocol itself, and the consent
form has some difficulties, too.
[Woman 1] Was it the language difficulty primarily, or—?
[Woman 2] There’s a lot of scientific terms in it, and I believe the committee wouldn’t
agree that there was enough description of the type and amount of blood that’s going
to be drawn.
[Woman 1] Okay.
Does it give them an idea of how many visits they have to make?
[Woman 2] I think it’s weak in that area, too.
[Woman 1] Okay, alright, okay.
What we gotta do—you talked to him?
[Woman 2] I talked with him several times, he’s enthusiastic, he’s a young investigator,
it’s the first time he’s tried to go through the committee.
I think right now, he doesn’t understand what they want, and he’s getting angry.
[Woman 1] Okay, so he’s at the hostile level now, so—?
[Woman 2] Almost.
Nice guy, I mean, he’s approachable.
[Woman 1] So you think I should call him, or—?
[Woman 2] I think that would be wise.
[Woman 1] Okay, alright, okay.
Let’s look at this behavioral one that’s a problem.
Okay.
This investigator wants to do this video tape, and I’m really concerned about, you know,
whether the people will know that he might use it for teaching purposes.
I don’t want him to be tempted to do that.
[Woman 2] I think it’s gonna be difficult to explain that to this fellow.
He’s already upset because he feels that the IRB is interfering with his work.
He wants to go ahead, and— [Woman 1] So you’re afraid if he tells them,
that he won’t be able to get people to participate, or—?
[Woman 2] I think he’s afraid of that, I don’t think he wants the consent form to
be any longer than it is.
[Woman 1] Okay, alright.
[Woman 2] I also think…
[Man 1: Edmund Pellegrino] I’m Edmund Pellegrino, Director of the Kennedy Institute for Ethics
at Georgetown University, and professor of medicine.
The comments you just heard reflect some of the common confusions and misunderstandings
about the functions of an IRB and the criteria an IRB uses to evaluate a protocol.
These comments are typical of the viewers of the scientific community, of the people
who direct research, and even the general public.
The IRB is carrying out an important moral and social responsibility.
Scientific research involving human volunteers is permitted by society to advance medical
knowledge for the benefit of all.
But if we are to continue to have that privilege, investigators must always stress the safety
of the volunteer, and the evaluation of the benefits gained.
The process of review, therefore, is designed first, to protect the subject; second, to
provide guidance to the design and experiment that will produce the results being sought.
The IRB process also assures society that those who are knowledgeable, but not immediately
involved, will independently review the experiment, give it approval, and provide assurances that
society’s moral mandate will be fulfilled.
What we will be seeing today is the review of a specific protocol designed to investigate
the effects of strenuous exercise on blood clotting.
The subjects will be normal volunteers.
They will be subjected to a series of examinations involving the drawing of blood, underwater
weighing, exercise on a treadmill, monitoring of cardiovascular and respiratory function.
The benefit to the volunteers will be minimal; by and large, the significance of the experiment
lies in the information it will provide for our understanding of normal exercise and its
effect on blood clotting and heart disease.
Let’s look now at the criteria the IRB will be using to evaluate this protocol.
We want to examine the criteria themselves, the way they actually work, and what their
purposes are.
[music interlude] First, the risks to the subject must be reasonable,
in relationship to the benefits to the subject, and the importance of the knowledge to be
obtained by the research.
The risks themselves must be kept to the minimum possible to achieve the purposes of the research.
There must be an equitable selection of subjects.
Informed consent must be obtained and documented, to safeguard the right of the subject to accept
or refuse participation in the study.
The privacy and confidentiality of the subject must be safeguarded.
There must be a continuous monitoring of the data.
In January of 1981, the Food and Drug Administration and the Department of Health and Human Services
issued the regulations that now govern the performance of research involving human volunteers,
the aim of the regulation being to protect those volunteers in the process of the clinical
investigations.
For the next few moments, let’s look at these criteria in a little more detail.
First, we must look at the protocol.
It must be scientifically sound.
It must be properly designed so that the knowledge being sought will, in fact, be obtained, and
the methods will yield the knowledge that is sought, and the knowledge itself must have
an importance for understanding human health or human behavior.
We must always remember we are exposing human subjects to a certain number of risks.
We have to have some kind of a moral sanction to do that.
If we were to start out with protocol, for example, that had certain scientific weaknesses,
one that wasn’t properly designed, then we’d be unnecessarily exposing people to
risks.
The Institutional Review Board has a responsibility to assure itself that, in fact, the criteria
of scientific probity have been fulfilled.
It needs evidence of that fact.
That, in itself, is also a moral requirement.
We have to look at the whole protocol from the subject’s point of view as well.
If you were a subject, you would want to know if the information to be gained would be worthwhile
for yourself or for some other person.
The subject cannot give valid consent unless he feels the risks are worth running.
So, whether it’s biomedical research or behavioral research, the first criterion is
exactly the same: important scientific knowledge must be obtained, and the generally accepted
canons of good scientific research must be fulfilled.
Now the second criterion.
What are the risks?
We have to admit that in every experiment involving humans, clinical and behavioral,
there is some risk of pain, discomfort, or even harm to the volunteer.
Every effort must be made to minimize risk.
Even though we have a very significant possibility of helping someone, we would have to assure
ourselves and the IRB that the investigator had taken every possible precaution to reduce
those risks to the minimum necessary to fulfill the purpose of the research.
Has the research, for example, incorporated safeguards to protect against the risks?
Insofar as possible, does the researcher intend to use procedures already indicated for the
individual subject’s condition?
Selection of subjects is very important to avoid discrimination, or over-selection of
vulnerable subjects.
Here, the IRB should be interested in who is selected, and from what populations.
Are particularly the susceptible populations being chosen?
Prisoners, for example, students, older people, sick people, children, people with malignant
diseases, psychotic or emotionally disturbed persons, people for whom there are language
problems.
People who are particularly vulnerable must receive special protection.
Informed consent is the central ethical issue in experimentation.
Under no circumstances may we involve a human being in experimentation without his consent.
What do we mean by informed consent?
Informed consent means that the subject has to have a full disclosure of procedures, risks,
and benefits.
What is going to be done, for what reasons, what risks are there, what are the dangers,
the kind and the possibility of discomfort, the loss of time, perhaps even the loss of
dignity.
The benefits, the alternatives, all those circumstances that go along with being a research
subject, must also be made clear to the subject.
The investigator has the responsibility to ensure himself that the person does, in fact,
understand.
That means that we have to be dealing with competent individuals, or their legally authorized
representatives.
Persons who can perceive and process the information can make a decision which is their own, on
the basis of their own values, and express their decision clearly to us.
The decision must be free of coercion.
The individual truly must volunteer.
Throughout the entire experiment, subjects must know they have the right to discontinue,
to withdraw from the experiment at any time they wish to do so.
Once involved, subjects are sometimes afraid to withdraw.
The experiment has a certain momentum of its own; subjects need to be told that not only
do they have a right to refuse to participate, but they can withdraw at any time.
And they must be able to withdraw without being penalized for any agreed-upon fee or
associated treatment.
Society gives us a mandate to involve humans, because it’s the only way we can find out
about the effects of new drugs, new treatments, or new psychiatric maneuvers of various kinds.
Those new procedures have to be tried out in some human being, somewhere, sometime.
Before we can involve someone as the subject of an investigation, we must be sure to respect
their rights as a person.
Under all circumstances, privacy and confidentiality must be stringently safeguarded.
This means that the IRB must assure itself, both from the protocol and from the questioning
of the investigators, that any information detected about the volunteers will be kept
confidential, and limited to those who are authorized to know.
And the subject must be told who it is that has access to this information.
That information might be damaging, for example, to the person’s reputation, to his social
status, or even to his job.
The information itself might create anxiety for the subject.
Subject privacy and capacity to control his way of life must not, in any way, be compromised.
Throughout the entire experiment, the data must be monitored by the investigators or,
preferably, by some other group.
In the course of the experiment, it may become apparent that the treatment is so beneficial
that to continue to have controls would be doing a disservice to the controls.
Or the other way around: it may become evident that the drug is very toxic or ineffective.
Then it ought to be withdrawn before the study is finished.
In the case of behavioral research, emotional trauma to subjects may be such that the information,
even though significant, is not worth getting.
This means there must be continual feedback; every one of the criteria must be monitored
in the light of how the experiment is actually going.
Approval for an IRB is not unconditional.
These are the six criteria that form the basis upon which an IRB conducts its review.
Now, let’s turn to an actual experiment.
We’ll follow it from the time the investigators are preparing for IRB review, through to the
actual conduct of the experiment.